Process for preparing pyrano- and thiopyranoindole derivatives

ABSTRACT

Pyranoindole and thiopyranoindole derivatives characterized by having an amino(lower)alkyl radical attached to either or both the 1 and 9 position of a pyrano[ 3,4-b]indole or thiopyrano[3,4-b]indole nucleus are disclosed. The amino position of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives having the amino(lower)alkyl radical only at position 1 are further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The derivatives having the amino(lower)alkyl radical only at position 9 posses two substituents at position 1 and may be optionally substituted at position 3, 4, 5, 6, 7, and 8. The derivatives having an amino(lower)alkyl radical at both positions 1 and 9 are further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7 and 8. The pyrano- and thiopyranoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

This is a division of application Ser. No. 507,085, filed Sept. 18, 1974, now abandoned, which in turn is a division of Ser. No. 217,627 filed Jan. 13, 1972 and now U.S. Pat. No. 3,852,285, issued Dec. 3, 1974.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to novel pyranoindole and thiopyranoindole derivatives, to processes for their preparation and to intermediates used in these processes.

More specifically, the present invention relates to novel pyranoindole and thiopyranoindole derivatives possessing valuable pharmacologic properties. For example, these derivatives exhibit useful antidepressant properties at dosages which do not elicit undesirable side effects. Furthermore the present derivatives exhibit properties useful for the treatment and prevention of ulcers. The combination of these pharmacologic properties together with a low order of toxicity render the pyranoindoles and thiopyranoindoles of the invention therapeutically useful.

2. Description of the Prior Art

Only a rather limited number of reports dealing with pyrano[3,4-b]indole derivatives are available. In the few that do exist, pyranoindoles are treated more in the manner of chemical curiosities. For the most part these reports discuss the preparation of pyranoindoles in which the pyran portion thereof exists as a lactone. For example, see H. Plieninger, Chem. Ber., 83, 271 (1950) and S. Sakurai and T. Ito, Nippon Kagaku Zasshi, 78, 1665 (1957); [Chem Abstr., 54, 1488f (1960)].

The thiopyranoindoles of the prior art, for example, 5-(3-aminopropyl)-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole, M. E. Freed, et al., J. Med. Chem., 7, 628 (1964) are distinguished from the present compounds of this invention by having a different ring structure and by lacking substituents on the thiopyran ring.

SUMMARY OF THE INVENTION

The pyranoindole and thiopyranoindole derivatives of this invention are characterized by having an amino(lower)alkyl radical attached to a pyrano[3,4-b]indole or thiopyrano[3,4-b]indole nucleus. The preferred derivatives of this invention are represented by formula I, ##STR1## in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino, 4-(lower alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X is oxy or thio; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NU⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with the proviso that at least one of R⁷ and Y is --Alk--NR⁸ R⁹.

In the above definitions it is understood that Alk, R⁸ and R⁹ in each case are entitled to the full range of their definitions as listed above, so that Alk, R⁸ and R⁹ of Alk--NR⁸ R⁹ linked to position 9 need not necessarily be the same as Alk, R⁸ and R⁹ of Alk--NR⁸ R⁹ linked to position 1.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl and the like.

The term "phenyl(lower)alkyl" as used herein contemplates a phenylalkyl radical in which the alkyl portion thereof contains from one to four carbon atoms and includes benzyl, phenethyl, α-methylphenethyl and the like.

The term "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straight and branched chain alkanoyloxy radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The term "halo" as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.

The compounds of formula I are capable of forming acid addition salts with pharmaceutically acceptable acids. Such acid addition salts are included within the scope of this invention.

The acid addition salts are prepared by reacting the base form of the appropriate compound of Formula I with either one to four equivalents, depending on the number of basic nitrogens in the compound, or preferably with an excess of the approprite acid in an organic solvent, for example, ether or an ethanol-ether mixture. These salts, when administered to mammals, possess the same pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the base compounds. Among the acid addition salts suitable for this purpose are salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate, hydrobromide and hydrochloride. Both the base compounds and the salts have the distinct advantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of the compounds of formula I which result from asymmetric centers, contained therein. These isomeric forms are prepared by different methods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractional crystallization of the diastereoisomeric salts formed thereof, for instance, with d- or l- tartaric acid or D-(+)-α-bromocamphor sulfonic acid, are also included.

Antidepressant Activity

The useful antidepressant activity of the compounds of formula I and their acid addition salts with pharmaceutically acceptable acids are demonstrated in standard pharmacologic tests, such as, for example, the tests described by F. Hafliger and V. Burckhart in "Psychopharmacological Agents", M. Gordon, Ed., Academic Press, New York and London, 1964, pp. 75 - 83.

More specifically, as noted in the latter reference the antidepressant properties of a compound may be demonstrated by its capacity to antagonize the depresssant effects of reserpine. Furthermore, it is well documented that reserpine in animals produces a model depression which can be used for detecting antidepressant properties. Accordingly, the compounds of the present invention antagonize reserpine effects in mice at doses ranging from about 1 to 100 mg/kg. Several of the preferred compounds, for instance,

1-[(2-dimethylamino)ethyl] -1-methyl-1,3,4,9-tetrahydropyrano 3,4-b]indole oxalate (Example 309),

1-methyl-[3-(methylamino)propyl]-1,3,4,9-tetrahydropyrano-[ 3,4-b]indole oxalate (Example 310),

1-[3-(dimethylamino)propyl]-1-methyl-1,3,4,9-tetrahydropyrano-[ 3,4-b]indole oxalate (Example 312),

1-[2-(dimethylamino)ethyl]-1-propyl-1,3,4,9-tetrahydropyrano-[ 3,4-b]indole maleate (Example 330), and

1-[2-(dimethylaminoethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydropyrano-[ 3,4-b]indole maleate (Example 683),

antagonize the effects of reserpine in mice at dose ranges from about 1 to 15 mg/kg.

When the compounds of this invention are used as antidepressants in warm-blooded mammals, e.g. rats and mice, they may be used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generaly, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 0.1 mg to about 50 mg per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 0.5 mg to about 25 mg per kilo per day is most desirably employed in order to achieve effective results.

Antiulcer Activity

The compounds of formula I of this invention possess another useful pharmacologic property; that is, they are useful antiulcer agents. More particularly, the said compounds of this invention exhibit antiulcer activity in standard pharmacologic tests, for example, the test described by D. A. Brodie and L. S. Valitski, Proc. Soc. Exptl. Biol. Med., 113, 998 (1963), based on the prevention of stress-induced ulcers.

When the compounds of formula I are employed as antiulcer agents, they may be formulated and administered in the same manner as described above for their use as antidepressant agents.

Processes

For the preparation of the pyranoindole and thipyranoindole derivatives of this invention we prefer to use as starting materials the compounds of general formula II, ##STR2## in which R², R³, R⁴, R⁵ and R⁶ are as defined in the first instance and X¹ is hydroxy or mercapto.

The starting materials of formula II in which X¹ is hydroxy are either known, for example, tryptophol, described by H. R. Snyder and F. J. Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they are obtained by the following process: ##STR3##

With reference to this process phenylhydrazines of formula III and the hydroxyaldehyde of formula IV are reacted together according to the conditions of the "Fischer Indole Synthesis", for example, see P. L. Julian, E. N. Myer and H. C. Printy, "Heterocyclic Compounds", R. C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8 - 11, to form the desired starting material (II, X¹ = OH).

The phenylhydrazines of formula III are either known or are prepared according to known methods. A convenient method involves the diazotization of the appropriately substituted aniline to give the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example, "Rodd's Chemistry of Carbon Compounds", S. Coffey, Ed., Vol. I d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 44 - 49, or they are prepared according to known methods. A convenient method involves reduction of an appropriate lactone of formula ##STR4## with bis-(3-methyl-2-butyl)borane, H. G. Brown and D. B. Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin and I. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L. I. Zakharkin et al., Tetrahedron Letters, 2087 (1963). The appropriate lactones utilized in this condensation are either commercially available, for example, δ-valerolactone, α-methyl-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbooks, "Methoden der Organischen Chemie", Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561 - 852 or L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", cited above.

Alternatively, the starting materials of formula II in which R², R³ and R⁴ are hydrogen and X¹ is hydroxy are prepared by lithium aluminum hydride reduction (N. G. Gaylord, "Reduction with Complex Metal Hydrides", Interscience Publishers, Inc., New York, 1956, pp. 322 - 370) of compounds of formula V described by T. Y. Shen, U.S. Pat. No. 3,161,654, Dec. 15, 1964: ##STR5## wherein R¹⁸ is lower alkyl and R⁵ and R⁶ are as defined in the first instance.

In addition, convenient processes are available for the specific synthesis of certain starting materials of formula II. For example, starting materials of formula II in which R², R³, R⁴ and R⁵ are hydrogen and X¹ is hydroxy are obtained by reduction of the appropriate ethyl 3-indoleglyoxylate with lithium aluminum hydride, British Patent 778,823 and T. Nogrady and T. W. Doyle, Can. J. Chem., 42, 485 (1964). Starting materials of formula II in which R² and R⁴ are hydrogen, R³ and R⁵ are hydrogen or lower alkyl and X¹ is hydroxy are obtained by reacting indole or an appropriately substituted indole with ethylene oxide or lower alkyl substituted ethylene oxide according to the process of M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966).

The starting materials of formula II in which X¹ is mercapto and R², R³, R⁴, R⁵ and R⁶ are as defined in the first instance are obtained by the following process: The appropriate compound of formula II (X¹ = OH) described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or carbon tetrachloride, to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X¹ = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyanov, Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 67, 73474a (1967)], for converting 3-(2-bromoethyl)indole to indole-3-ethanethiol (II; R², R³, R⁴, R⁵ and R⁶ = H and X¹ = SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively, which on treatment with strong alkali for example, sodium or potassium hydroxide, is transformed into the corresponding bis-[ω-(3-indolyl)ethyl]disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II.

It should be noted that the preceding process may not be entirely practical for the preparation of the compounds of formula II in which X¹ is mercapto and R⁶ is hydroxy or loer alkanoyloxy. For this reason, the preferred starting materials or formula II for the ultimate preparation of the compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy and X is thio are the corresponding compounds of formula II in which R⁶ is benzyloxy, i.e., a hydroxyl with a protecting benzyl group or other suitable protecting group, see J. F. McOmie, "Advances in Organic Chemistry," Vol. 3, R. A. Raphael, et al, Ed., Interscience Publishers, New York, 1963, pp. 191 - 294. When the latter compounds are used as starting materials in this manner, they are first subjected to the process (II + VI→VII), described below. Subsequently, the benzyloxy group is removed by hydrogenation, in the presence of a catalyst, for example, 10% palladium on carbon, just prior to affording the desired corresponding compound of formula I in which R⁶ is hydroxy. The latter are converted, if desired, to the corresponding compound of formula I in which R⁶ is lower alkanoyloxy by conventional means, for example, by treatment with the appropriate lower alkanoic anhydride preferably in the presence of pyridine. Likewise, it should be noted that similar use of the starting materials of formula II in which X¹ is hydroxy and R⁶ is benzyloxy to obtain the corresponding compound of formula I in which R⁶ is hydroxy or lower alkanoyloxy is also preferred.

The above described starting materials of formula II in which R², R³, R⁴, R⁵, R⁶ and X¹ are as defined in the first instance are now subjected to a key reaction comprising the treatment of said starting materials with a compound of formula ##STR6## in which R¹ is as defined in the first instance and Z is selected from the group consisting of:

a. COOR¹⁹ and Alk¹ -- COOR¹⁹ in which R¹⁹ is hydrogen or lower alkyl and Alk¹ is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are hydrogen or lower alkyl,

b. CONR⁸ R⁹ and Alk¹ --CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as defined above,

c. CH₂ OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰ in which R²⁰ is hydrogen or lower alkyl and Alk¹ is as defined above,

d. Alk² --L in which Alk² is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CHR¹², CR¹⁰ R¹¹ CR¹² R¹³ CHR¹⁴ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CHR¹⁶ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above and L is halo,

e. Alk NR⁸ COR²¹ in which Alk and R⁸ are as defined in the first instance and R²¹ is hydrogen or lower alkyl containing from one to five carbon atoms,

f. Alk -- NO₂ in which Alk is as defined in the first instance, and

g. Lower alkyl and phenyl(lower)alkyl,

in the presence of an acid catalyst to yield the compounds of formula VII in which R¹, R², R³, R⁴ R⁵, R⁶, X and Z are as defined above and R⁷ is hydrogen. ##STR7##

Thereafter the appropriate compound of formula VII (R⁷ = H) is converted to the desired pyranoindole of formula I according to the processes described hereinafter.

In practising the condensation (II + Vi →VI) we have found it preferable to use a solvent as a reaction medium. Any solvent inert to the reaction conditions may be used. Suitable solvents includes aromatic hydrocarbon, for example benzene, or toluene, ethers and cyclic ethers, for example diethyl ether, dioxan, or tetrahydrofuran, halogenated hydrocarbons, for example methylene dichloride, or carbon tetrachloride and the like. Benzene and tetrahydrofuran are especially convenient and practical for this use. A variety of suitable acid catalysts may be used for this condensation, for example, the type of catalyst used in a Friedel-Crafts reaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid, sulfuric acid and the like. p-Toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalysts used is not especially critical and may range from 0.01 molar equivalents to 100 molar equivalents; however, a range of from 0.1 to 10 molar equivalents is generally preferred. The time of the reaction may range from 10 minutes to 60 hours, with the preferred range being from one-half to 24 hours. The temperature of the reaction may range from 20° C. to the boiling point of the reaction mixture. Preferred temperature ranges include 20° to 120° C.

A more detailed description of the preparation of the above intermediate compounds of formula VII and a description of their subsequent conversion to pyranoindole and thiopyranoindole derivatives of formula I are disclosed below. For convenience these descriptions are catagorized into sections according to the group selected for Z for the intermediate.

A. Preparation and Conversion of Intermediates of Formula VII (Z = COOR¹⁹ and Alk¹ --COOR¹⁹)

Intermediates of formula VII (Z = COOR¹⁹ and Alk¹ -- COOR¹⁹ in which R¹⁹ is hydrogen or lower alkyl and Alk¹ is as defined in the first instance, R⁷ is hydrogen and R¹ R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance) are readily obtained by the condensation (II+VI→VII) by using ketoacids or ketoesters of formula ##STR8## in which R¹ is as defined in the first instance and Z is COOR¹⁹ or Alk¹ -- COOR¹⁹ as defined above together with the starting material of formula II.

Generally comparable yields of product are obtained in this process when either the ketoacid or the corresponding ketoester is used. However, in the case where it is desired to prepare an acid compound of formula VII(R⁷ = H) in which Z is Alk¹ COOR¹⁹ wherein Alk¹ is CR¹⁰ R¹¹ and R¹⁹ is hydrogen (i.e., an acid intermediate of formula VII), it is preferable to first condense the appropriate β-ketoester of formula VI rather than the corresponding β-ketoacid and then hydrolyze the resulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often more convenient to prepare the acid compounds of formula VII(R⁷ =H) by using the ketoester instead of the ketoacid in this process and then hydrolyze the resulting ester product to the desired acid, the reason being simply that the ketoesters are generally more readily available either commercially or by synthesis.

The hydrolysis of compounds of formula VII(R⁷ =H) in which Z is COOR¹⁹ or Alk¹ COOR¹⁹ wherein Alk¹ is as defined in the first instance and R¹⁹ is lower alkyl, i.e. ester intermediates of formula VII(R⁷ =H), to their corresponding acids of formula VII (R⁷ = H) is readily effected by treatment with a suitable alkali, for example, potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol or by treatment with lithium iodide in a suitable organic solvent, for example, collidene, see L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis," John Wiley and Sons, Inc., New York, 1967, pp. 615 - 617.

The α-, β-, γ- and δ-ketoacids and -ketoesters of formula VI are either known, for example, ethyl pyruvate, levulinic acid, ethyl α,α-dimethylacetoacetate, and β,β-dimethyllevulic acid or they are prepared by known methods described in general organic chemistry textbooks. For example, a comprehensive review on the properties and preparation of such α-, β-, γ- and δ-ketoacids and -ketoesters may be found in "Rodd's Chemistry of the Carbon Compounds," cited above, Vol. Id, pp. 226 - 274.

Thereafter these intermediate acids and esters of formula VII(R⁷ = H) are converted to compounds of formula I in which R¹, R², R³, R⁴, R⁵ R⁶, R⁷ and X are as defined in the first instance and Y is -Alk-NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance. This conversion is accomplished by amidation, reduction and if desired N-alkylation of the indolic nitrogen. The order of these steps is not critical. However, we have found the following sequence of these steps to be both convenient and practical.

First, when it is desired to prepare the derivatives of the latter group of compounds of formula I in which R⁷ is H, i.e., N-alkylation of the indolic nitrogen is not desired, either the above acid intermediate or ester intermediate may be employed.

In the case where the acid intermediate of formula VII(R⁷ = H) is employed, said acid is subjected to amidation by treatment with a lower alkyl chloroformate, preferably ethyl chloroformate, in the presence of triethylamine, affording the corresponding mixed anhydride, which is converted by treatment with the appropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance, for example, ammonia, methylamine or dimethylamine, to yield the corresponding amide of formula VII in which Z is CONR⁸ R⁹ or Alk¹ CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the ester intermediates of formula VII (R⁷ = H) with the appropriate amine according to known amidation methods, for example, see A. L. F. Beckwith in "The Chemistry of Amides", J. Zalicky, Ed., Interscience Publishers, New York, 1970, pp. 96 - 105.

Secondly, the amides so obtained are reduced with a suitable complex metal hydride to yield the desired pyranoindoles and thiopyranoindoles. Examples of suitable complex metal hydrides are lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride. Lithium aluminum hydride is preferred.

On the other hand when it is desired to prepare the compounds of formula I of the above group in which R¹ R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is lower alkyl, or lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl and Y is --Alk--N R⁸ R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance, the acid or ester intermediate of formula VII(R⁷ = H) are first subjected to N-alkylation by treatment with a molar excess of the appropriate organic halide, namely a lower alkyl halide, lower alkenyl halide, propargyl halide, phenyl(lower)alkyl halide or amino(lower)alkyl halide, respectively, in an inert solvent in the presence of a proton acceptor. Suitable inert solvent include tetrahydrofuran, benzene, toluene and dimethylformamide. Suitable proton acceptors include sodium hydride, alkali metal carbonate and triethylamine. Preferred conditions for effecting this N-alkylation include the use of sodium hydride as a proton acceptor and tetrahydrofuran as an inert solvent. Although the optimum temperature and reaction time will vary depending on the reactants employed, the reaction is generally performed at the boiling point of the reaction mixture for a period of 30 minutes to 48 hours.

The lower alkyl halides, lower alkenyl halides, propargyl halide, phenyl(lower)alkyl halides and aminoalkyl(lower)halides employed herein are either known, for example, ethyl bromide, allyl bromide and dimethylaminoethyl chloride, or they are prepared by known methods, usually by the treatment of the corresponding alcohols with a halogenating agent, for instance, thionyl chloride, see D. J. Collins and J. J. Hobbs, Aust. J. Chem., 20, 1413 (1967) and R. B. Moffett, J. Org. Chem., 14, 862 (1949).

In this manner, the corresponding N-alkylated derivatives of the above acid and ester derivatives of formula VII are obtained. Thereafter these derivatives are subjected to the amidation and reduction steps according to the conditions described hereinabove in this section, to afford the desired compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl, or amino(lower)alkyl.

Although the above sequence of steps for the conversion of the acid and ester intermediates of formula VII (R⁷ = H) to the above desired pyranoindoles is convenient and efficacious, a change in the order of the steps whereby the amides of formula VII (R⁷ = H) are treated with the appropriate organic halide according to the N-alkylation conditions described above, followed by reduction with a complex metal hydride, as described above, also affords the above desired compounds of formula I, in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl, described above, of the resulting corresponding amide derivative in which the indolic nitrogen is alkylated, also affords the above desired compounds of formula I, in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower) alkyl or amino(lower)alkyl.

Furthermore, another change in the order of the steps for preparing the latter compounds of formula I is realized by N-alkylation, as described above, of the corresponding compounds of formula I in which R⁷ is hydrogen, described above. In this case when the starting material employed is a pyranoindole or thiopyranoindole of formula I in which Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen and R⁹ is hydrogen or lower alkyl, i.e., a primary or secondary amine function is present in the molecule in addition to the indolic nitrogen, it is expedient to use only one molar equivalent of the appropriate organic halide to avoid alkylation of the primary or secondary amine if so desired.

Another aspect of the present intermediates of formula VII relates to their conversion to compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as described in the first instance and Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen and R⁹ is lower alkyl, i.e. secondary amines. When it is desired to prepare the latter compounds a modification involving the protection of the secondary amine with a benzyl group or other suitable protecting group, see J. F. McOmie, cited below is especially convenient. For example, the aforementioned acid or ester intermediate of formula VII is reacted with an amine of formula HNR⁸ R⁹ in which R⁸ is benzyl and R⁹ is lower alkyl according to the amidation step described above. The resulting amide is N-alkylated on the indolic nitrogen, if desired, and then reduced with a complex metal hydride according to the above procedures. Thereafter the benzyl group is removed by hydrogenolysis in the presence of a catalyst, preferably 10% palladium on carbon, to afford the desired secondary amine compounds of formula I.

Still another modification relates to a more general reduction of the above amides of formula VII in which Z is CONR⁸ R⁹ or Alk¹ -CONR⁸ R⁹ wherein Alk¹, R⁸ and R⁹ are as defined in the first instance. In other words this modification is applicable to the reduction of tertiary, secondary and primary amides, described herein, and is a preferred modification for the reduction of the latter two. In practising this modification, the aforementioned amide of formula VII is treated with triethyloxonium fluoroborate or dimethyl sulfate, see H. Bredereck, et al., Chem. Ber., 98, 2754 (1965), in an inert solvent, for example, methylene dichloride, whereby the corresponding iminoether fluoroborate or methyl sulfate salt is obtained, respectively. Subsequent reduction of the salt thus obtained with a complex metal hydride, similar to the reduction described previously for the amides, yields the corresponding compounds of formula I. Alternatively, the above fluoroborate or methyl sulfate salt derived from a secondary or primary amide is decomposed by base treatment, for example, with 10% sodium hydroxide or triethylamine, to give the corresponding iminoether which is then reduced in a like manner to the desired compound of formula I.

When applying the aforementioned steps in the preparation of compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy, it is preferable to use corresponding intermediates in which R⁶ is benzyloxy followed by the appropriate transformations as noted previously to yield the desired compounds of formula I.

b. Preparation and Conversion of Intermediates of Formula VII (Z = CONR⁸ R⁹ and Alk¹ --CONR⁸ R⁹).

The intermediates of formula VII in which R⁷ is hydrogen and Z is CONR⁸ R⁹ and Alk¹ --CONR⁸ R⁹ wherein R⁸, R⁹ and Alk¹ are as defined in the first instance, described in the previous section, are also obtained directly by utilizing the appropriate starting materials of Formula II and α-, β-, γ- or δ-ketoamides of formula ##STR9## in which R¹ is as defined above and Z is CONR⁸ R⁹ or Alk¹ --CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as defined above. The ketoamides required for this condensation are either known, for example, pyruvamide or α,α-dimethylacetoacetamide, or they are prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds," cited above, Vol. 1d, pp. 226-274.

Thereafter these amides are converted by the reduction process, described above, to the compounds of formula I in which R¹ R², R³, R⁴, R⁵, R⁶, and X are as defined in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --Ch₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance.

c. Preparation and Conversion of Intermediates of Formula VII (Z = CH₂ OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰)

Intermediates of formula VII in which R⁷ is hydrogen and Z is CH₂ OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰ in which Alk¹ and R²⁰ are as defined in the first instance, are obtained when a starting material of formula II is condensed with a ketoalcohol lower alkanoic acid ester of formula R¹ COCH₂ OCOR²⁰ or R¹ CO--Alk¹ --CH₂ OCOR²⁰ in which R¹, Alk¹ and R²⁰ are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II+VI→VII). The ketoalcohol lower alkyl esters are either known, for example, acetonyl acetate or 5-acetoxypentan-2-one, or are prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds," cited above, Vol. 1d, pp. 49-54.

These intermediates of formula VII may then be utilized for the preparation of compounds of formula I of this invention in the following manner. The intermediate is hydrolyzed with an aqueous alcoholic solution of a suitable alkali, for example, sodium hydroxide in aqueous methanol to afford the corresponding primary alcohol. The primary alcohol is then oxidized to the corresponding aldehyde. Although a variety of methods are known for the oxidation of a primary alcohol to its corresponding aldehyde, see for example, "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1c, pp. 4 - 10, we have found that the method of K. E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc., 87, 5670 (1965), using N,N-dicyclohexylcarbodimide and dimethyl sulfoxide in the presence of a suitable acid, for example, trifluoroacetic acid, is both efficacious and convenient. Thereafter the aldehyde is reacted with an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance to give the corresponding Schiff base, which is reduced with sodium borohydride, see E. Schenker, Angew. Chem., 73, 81 (1961), to yield compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --CH₂ and R⁸ and R⁹ are as defined in the first instance.

Alternatively, the latter compounds of formula I are obtained by converting the above corresponding alcohol to a reactive intermediate such as the corresponding halide, mesylate or tosylate, which are then reacted with a two molar excess of an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance. Preferably this reaction is performed in a suitable inert solvent, for example, tetrahydrofuran, at the boiling point of the reaction mixture for a period of 8 to 24 hours. In connection with alkylations of amines of formula HNR⁸ R⁹ in which R⁹ is hydrogen and R⁹ is lower alkyl as disclosed herein, it is generally preferable to perform the alkylation with the corresponding N-benzyl derivative of said amine, i.e., an amine of formula NHR⁸ R⁹ in which R⁸ is benzyl and R⁹ is lower alkyl. Thereafter, when all appropriate transformation have been performed, the N-benzyl group is removed by hydrogenolysis with a catalyst, preferably 10% palladium on carbon, to give the desired compounds of formula I.

Thereafter, and if desired, these latter compounds of formula I are converted to their corresponding derivatives in which R⁷ lower alkyl, lower alkenyl, propargyl, phenyl(lower)allyl or amino(lower)alkyl by N-alkylation with one molar equivalent of the appropriate or organic halide in the manner described for the N-alkylation in section (a).

Alternatively, the above aldehyde is oxidized with a suitable oxidizing agent to yield the corresponding acid intermediates of formula VII (R⁷ = H) described in section (a). Although a variety of suitable oxidizing agents may be used for this purpose, for example, silver oxide, alkaline permanganate, hydrogen peroxide, we prefer to use silver oxide according to the method of M. Delepine and P. Bonnet, Compt. rend., 149, 39 (1909).

Again alternatively, the above aldehyde is converted to its oxime which on reduction with a complex metal hydride yields the corresponding primary amine of formula I in which R¹, R², R³ R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk--¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are hydrogen.

If desired those latter primary amine compounds of formula I may be N-alkylated on the indolic nitrogen in the manner described above with a molar equivalent of the appropriate organic halide to give the corresponding compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or Alk--NR⁸ R⁹ wherein Alk, R⁸ and R⁹ are as defined in the first instance.

In turn these latter compounds of formula I may be further N-alkylated on the nitrogen of the primary amine with the appropriate lower alkyl halide to the corresponding compounds of formula I in which Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen or lower alkyl and R⁹ is lower alkyl (i.e. secondary or tertiary amines with respect to Y). In this case depending on the particular derivative desired the N-alkylation is effected with one or two moles of the alkyl halide to give respectively the secondary (R⁸ = H and R⁹ = lower alkyl with respect to Y)or tertiary amine (R⁸ = R⁹ = lower alkyl with respect to Y). On the other hand the N-alkylation may be effected in two steps introducing a different alkyl group each time to afford the corresponding tetiary amine in which R⁸ and R⁹ are different lower alkyls with respect to Y.

When it is desired to prepare the above tertiary amine compounds in which R⁸ or R⁹ are either or both methyl, an alternative alkylation method comprises reacting the appropriate corresponding primary or secondary amine with an aqueous mixture of a substantial excess of formaldehyde and formic acid according to the conditions of the Eschweiler-Clarke reaction, see M. L. Moore, Organic Reactions, 5, 301 (1949), whereby N-methylation is effected.

Another N-alkylation method which is applied to the above primary and secondary amines involves acylation with a lower alkanoic anhydride or acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines are used to prepare compounds of formula I in which Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂ and R⁸ and R⁹ together with the nitrogen atom to which they are joined from a heterocyclic amine radical as defined in the first instance. When used in this manner the primary amines are subjected to known N-alkylation methods, for example, see method J in Moffett, cited above, with the appropriate α,ω-dibromides, for example, tetramethylene dibromide, pentamethylene dibromide, bis(2-chloroethyl)ether, bis(2-chloroethyl)benzylamine followed by hydrogenation in the presence of 10% palladium on carbon to remove the protecting benzyl group, a bis(2-chloroethyl)lower alkylamine or a bis(2-chloroethyl)-N-[hydroxy(lower)alkyl]amine, to give the corresponding, desired compound of formula I wherein Y is an amino(lower)alkyl in which the amino portion thereof is pyrrolidino, piperidino, morpholino, piperazino, 4-(lower)alkyl-1-piperazinyl or 4-[hydroxy(lower)alkyl]-1-piperazinyl, respectively.

If during the above N-alkylations it is desired to protect primary or secondary amine functions that are present in the R⁷ portion of compounds of formula I, such protection may be afforded by the use of appropriate protecting groups, for example, a benzyl group; see also, J. F. W. McOmie in "Advances in Organic Chemistry," Vol. 3, R. A. Raphael, et al., Ed., Interscinece Publishers, New York, 1963, pp. 191-294.

d. Preparation and Conversion of Intermediates of Formula VII (Z = Alk² --L).

Intermediates of formula VII in which R⁷ is hydrogen and Z is Alk² --L wherein Alk² and L are as defined in the first instance, are obtained when a starting material of formula II is condensed with a β,γ- or δ-haloketone of formula R¹ CO--Alk² --L in which R¹, Alk² and L are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II+VI→VII). The haloketones are either known, for example, 4-chlorobutan-2-one, or they are prepared by known methods, for instance, see "Rodd's Chemistry of Carbon Compounds," cited above, Vol. 1c, pp. 70-71 and "Methoden der Organischen Chemie," Houben-Weyl, E. Muller, Ed., Vol. V/3, Geor Thieme Verlag, Stuttgart, 1962, pp. 511-1076.

Thereafter these intermedates of formula VII are treated with a two molar excess of an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance to yield the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as described in the first instance, R⁷ is hydrogen and Y is --Alk--NR⁸ R⁹ in which Alk is Alk² as defined in the first instance and R⁸ and R⁹ are as defined in the first instance. Preferred conditions for this reaction include the use of a suitable inert solvent, for example, tetrahydrofuran, temperatures ranging from 40°- 100° C. or at the boiling point of the reaction mixture and a reaction time of from 8 to 24 hours.

If desired the latter pyranoindoles and thiopyranoindoles may be N-alkylated on the indolic nitrogen with an appropriate lower alkyl halide or aminoalkyl halide according to the method described for the N-alkylation of the pyranoindoles and thiopyranoindoles in section (a).

e. Preparation and Conversion of Intermediates of Formula VII (Z = AlkNR⁸ COR²¹)

Intermediates of formula VII in which R⁷ is hydrogen and Z is AlkNR⁸ COR²¹ wherein Alk, R⁸ and R²¹ are as defined in the first instance are readily obtained by the condenation (II+VI→VII) by using ketoamides of formula ##STR10## in which R¹, Alk, R⁸ and R²¹ are as defined in the first instance together with the appropriate starting material of formula II.

The ketoamides used herein are either known, for example, formamidoacetone [A. Treibs and W. Sutter, Chem. Ber., 84, 96 (1951)] and see [R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948)] or they are prepared by known procedures, for example, see "Methoden der Organischen Chemie", cited above, Vol. XI/1, 1957, especially pp. 58-62, 285-289 and 508-509, and F. F. Blicke, Organic Reactions, 1, 303 (1942).

Thereafter, reduction with a complex metal hydride and if desired N-alkylation of the indolic nitrogen as described in section (a) converts the instant intermediates of formula VII to pyranoindoles of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X are as defined in the first instance and Y is AlkNR⁸ R⁹ in which Alk and R⁸ are as defined in the first instance and R⁹ is lower alkyl.

f. Preparation and Conversion of Intermediates of Formula VII (Z = Alk -- NO₂)

Intermediates of formula VII in which R⁷ is hydrogen and Z is Alk-NO₂ wherein Alk is as defined in the first instance, are obtained by the condensation (II+VI→VII) when the starting materials of formula II and appropriate α-, β-, γ- , and δ-nitroketones of formula ##STR11## in which R¹ and Alk are as defined in the first instance are employed therein in the presence of a suitable acid catalyst. In this case trifluoroacetic acid is the preferred acid catalyst.

The nitroketones used herein are either known, for example, 1-nitro-2-propanone, N. Levy and C. W. Scaife, J. Chem. Soc., 1100, (1946) and 5-nitro-2-hexanone, H. Shechter, et al., J. Amer. Chem. Soc. 74, 3664 (1952) or they are prepared by known methods, for example, see Levy, and Scaife, cited above, Shechter, et al. cited above, "Rodd's Chemistry of Carbon Compounds," cited above, Vol. 1c, pp. 71-72 and "Methoden der Organischen Chemie," cited above, Vol. X/1, 1971, p. 203.

Thereafter, these intermediates of formula VII are reduced with a complex metal hydride, preferably lithium aluminum hydride, to afford the pyranoindoles of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, Y is hydrogen and Z is --Alk--NR⁸ R⁹ in which Alk is defined in the first instance and R⁸ and R⁹ are hydrogen.

If desired the latter compounds may be N-alkylated according to the methods described in section (c) to give the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined in the first instance and Y is Alk-NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the first instance.

g. Preparation and Conversion of Intermediates of Formula VII (Z = lower alkyl or phenyl(lower)alkyl)

Intermediates of formula VII (Z = lower alkyl or phenyl(lower)alkyl, R⁷ is hydrogen and R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance) are readily obtained by the condensation (II+VI→VII) by using the starting materials of formula II and the ketones of formula ##STR12## in which R¹ is as defined in the first instance and Z is lower alkyl or phenyl(lower)alkyl.

The ketones used herein are either available commercially, for example, acetone or phenylacetone, or they are prepared by conventional methods, for example, see P. Karrer, "Organic Chemistry," 2nd. ed., Elsevier Publishing Co., Inc., New York, 1946, pp. 149-169 and V. Migrdichian, "Organic Synthesis," Vol. 1, Reinhold Publishing Corp., New York, 1957, pp. 100-129.

These intermediates of formula VII are converted to the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is --(Alk)--NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the first instance and Y is lower alkyl or phenyl(lower)alkyl by N-alkylation of the indolic nitrogen with the appropriate amino(lower)alkyl halide according to the method of N-alkylation described in section (a).

Finally, it is the intention to cover all changes and modifications of the embodiment of the invention herein chosen for the purpose of disclosure which are within the scope and spirit of this invention. Such changes and modification include those variations which depend on well known interconversions of amines, amides, acids and esters of alternation of the order of the steps in the processes disclosed herein.

For example, the act of subjecting the corresponding derivative of the starting material of formula II in which the indolic nitrogen is alkylated with a lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl, to condensation with an appropriate compound of formula VI according to the conditions of the key reaction taught in this present disclosure to yield the corresponding intermediate compound of formula VII in which the indolic nitrogen is so alkylated would not depart from the scope or spirit of this invention.

The following examples illustrate further this invention.

EXAMPLE I 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O and Z = CH₂ COOH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b-]indole-1-acetic acid ethyl ester, as an oil, ν_(max) ^(CHCl).sbsp.3 1715 cm⁻¹.

Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H₂ O and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150° - 152° C., ν_(max) ^(CHCl).sbsp.3 3325 and 1705 cm⁻¹.

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indoleacetic acid methyl ester, m.p. 87° - 90° C. after recrystallization from benzene-hexane, is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propyl ester is obtained as the ester.

EXAMPLE 2 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-PROPIONIC ACID (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Z = CH₂ CH₂ COOH)

A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70° C. for 11/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na₂ SO₄) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104° - 110° C., nmr (CDCl₃) δ 1.47 (3H), 21.8 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1.H).

The above title compound is also obtained by following the procedure of Example 1 but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, m.p. 116° - 118° C., ν_(max) ^(CHCl).sbsp.3 1716 cm⁻¹, after crystallization from benzene-petroleum ether, is obtained as the ester prior to hydrolysis.

EXAMPLE 3 1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = S AND Z = CH₂ COOH)

Indole-3-ethanediol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70° - 80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid, ν_(max) ^(CHCl).sbsp.3 1715 cm⁻¹.

This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147° - 149° C., nmr (CDCl₃) δ 1.86 (S, 3H), 306 and 812 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.

The procedures of Examples 1, or 3 are followed to prepare other compounds of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen and Z is COOR¹⁹ or Alk¹ --COOR¹⁹ wherein R¹⁹ and Alk¹ are as defined in the first instance. Examples of such compounds of formula VII are listed in Tables I and II. In each of these examples an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in the procedures of Examples 1 and 3. Note that in each of these examples the ester obtained prior to hydrolysis is a corresponding ester compound of formula VII.

Similarly, the procedure of Example 2 is used to prepare the products listed in Tables I and II. In this case an equivalent amount of the starting material of formula II, listed therein is used instead of the starting material of formula II described in Example 2 and an equivalent amount of the corresponding ketoacid of formula VI is used instead of the ketoester of formula VI listed therein.

                                      TABLE I                                      __________________________________________________________________________                                   Ketoester of          Product: [(prefix                                        Formula VI            listed                                                                         below)-1,3,4,9-             Starting Material of Formula II                                                                              ##STR13##            Tetrahydropyrano-                                                              [3,4-b]indole-1-                                                               (Suffix Listed                                                                 Below)                     Example                                                                             R.sup.2                                                                             R.sup.3                                                                           R.sup.4                                                                             R.sup.5                                                                            R.sup.6                                                                              X R.sup.1                                                                             Alk.sup.1CO   R.sup.19                                                                          Prefix//Suffix             __________________________________________________________________________     4    H    H  H    H   H     O CH.sub.3                                                                            CO            C.sub.2 H.sub.5                                                                   1-methyl//carboxylic                                                           acid                       5    CH.sub.3                                                                            H  H    H   H     O C.sub.2 H.sub.5                                                                     CO            C.sub.2 H.sub.5                                                                   1-ethyl-3-methyl//                                                             carboxylic acid            6    n-C.sub.3 H.sub.7                                                                   H  H    H   5-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CO            CH.sub.3                                                                          1,3-diisopropyl-6-                                                             methyl//carboxylic                                                             acid                       7    CH.sub.3                                                                            CH.sub.3                                                                          H    H   5-OH  O CH.sub.3                                                                            CO            CH.sub.                                                                           1,3,3-trimethyl-6-                                                             hydroxy//carboxylic                                                            acid                       8    H    H  H    H   7-C.sub.2 H.sub.5                                                                    O n-C.sub.3 H.sub.7                                                                   CO            CH.sub.3                                                                          8-ethyl-1-propyl//                                                             carboxylic acid            9    H    H  i-C.sub.3 H.sub.7                                                                   H   H     O                                                                                 ##STR14##                                                                          CO            CH.sub.3                                                                          1-cyclopropyl-4-isopro                                                         - pyl//carboxylic                                                              acid                       10   CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    H     O                                                                                 ##STR15##                                                                          CO            CH.sub.3                                                                          1-cyclopentyl-4,4-                                                             diethyl-3,3-dimethyl//                                                          carboxylic acid           11   H    H  CH.sub.3                                                                            H   H     O CH.sub.3                                                                            CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1,4-dimethyl//acetic                                                           acid                       12   H    H  H    H   H     O C.sub.2 H.sub.5                                                                     CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1-ethyl//acetic acid                                                           m.p. 137-140°                                                           C.                         13   H    H  H    H   H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1-propyl//acetic                                                               acid                                                                           m.p. 148-151°                                                           C.                         14   H    H  H    H   H     O i-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1-isopropyl//acetic                                                            acid, m.p. 150-                                                                152° C.             15   CH.sub.3                                                                            H  H    H   H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   3-methyl-1-propyl//                                                            acetic acid;                                                                   m.p. 75-80°                                                             C.                                                                             (Isomer A), m.p. 146                                                           -                                                                              148° C.                                                                 (Isomer B).                16   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     CH.sub.3                                                                           H     O C.sub.2 H.sub.5                                                                     CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1,4-diethyl-3-methyl//                                                         8                                                                              acetic acid,               17   H    H  H    H   H     O CH.sub.3                                                                            CH(CH.sub.3)CO                                                                               C.sub.2 H.sub.5                                                                   α,1-dimethyl//ac                                                         etic                                                                           acid; m.p.                                                                     154-156° C.                                                             (Isomer A), m.p.                                                               163-                                                                           165° C.                                                                 (Isomer B).                18   H    H  H    H   H     O                                                                                 ##STR16##                                                                          C(CH.sub.3).sub.2 CO                                                                         C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.                                                         alpha.- dimethyl//acet                                                         ic acid                    19   H    H  H    H   H     O t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1-t-butyl//acetic                                                              acid                                                                           m.p. 210-212°                                                           C.                         20   H    H  H    H   H     O n-C.sub.4 H.sub.9                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   1-butyl//acetic                                                                acid,                                                                          m.p. 124-127°                                                           C.                         21   H    H  H    H   7-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   8-methyl-1-propyl//                                                            acetic acid m.p.                                                               127-                                                                           128° C.             22   H    H  H    H   5-Br  O C.sub.2 H.sub.5                                                                     CH.sub.2 CO   C.sub.2 H.sub.5                                                                   6-bromo-1-ethyl//                                                              acetic acid m.p.                                                               182-184° C.         23   H    H  H    H   5-OCH.sub.3                                                                          O CH.sub.3                                                                            CH.sub.2 CO   CH.sub.3                                                                          6-methoxy-1-methyl//                                                           acetic acid, m.p.                                                              142-143° C.         24   H    H  H    H   5-OCOCH.sub.3                                                                        O CH.sub.3                                                                            CH.sub.2 CO   C.sub.2 H.sub.5                                                                   6-acetoxy-1-methyl//                                                           acetic acid, m.p.                                                              142-143° C.         25   H    H  H    H   5-benzyl-                                                                            O CH.sub.3                                                                            CH.sub.2 CO   C.sub.2 H.sub.5                                                                   6-benzyloxy-1-methyl//                                                         N                                                oxy                           acetic acid, m.p.                                                              163.5° C.           26   H    H  H    H   4-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   5-methyl-1-propyl//                                                            acetic acid, m.p.                                                              177-178° C.         27   H    H  H    H   6-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   7-methyl-1-propyl//                                                            acetic acid, m.p.                                                              157-158° C.         28   H    H  H    H   5-NO.sub.2                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   6-nitro-1-propyl//                                                             acetic acid, m.p.                                                              119-120° C.         29   H    H  CH.sub.3                                                                            CH.sub.3                                                                           H     O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO   C.sub.2 H.sub.5                                                                   4,4-dimethyl-1-                                                                propyl//acetic acid,                                                           m.p. 184-185°                                                           C.                         30   CH.sub.3                                                                            CH.sub.3                                                                          H    H   5-OC.sub.2 H.sub.5                                                                   O                                                                                 ##STR17##                                                                          CH(C.sub.2 H.sub.5)CO                                                                        C.sub.2 H.sub.5                                                                    ##STR18##                 31   CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    6-C.sub.2 H.sub.5                                                                    O                                                                                 ##STR19##                                                                          C(CH.sub.3).sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    ##STR20##                 32   CH.sub.3                                                                            H  n-C.sub.3 H.sub.7                                                                   n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                  O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CO                                                                               C.sub.2 H.sub.5                                                                   α,3-dimethyl-1-e                                                         thyl-                                                                          4,4,5-tripropyl//                                                              acetic acid                33   H    H  H    H   H     O n-C.sub.3 H.sub.7                                                                   C(CH.sub.3).sub.2 CO                                                                         C.sub.2 H.sub.5                                                                   α,α-dimeth                                                         yl-1-                                                                          propyl//acetic acid        34   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                    O t-C.sub.4 H.sub. 9                                                                  C(i-C.sub.3 H.sub.7).sub.2 CO                                                                C.sub.2 H.sub.5                                                                   1-t-butyl-α,.alp                                                         ha.-                                                                           diisopropyl-3,3,4,4,5-                                                         N                                                                              pentaethyl//acetic                                                             acid                       35   H    H  H    H   4-I   O i-C.sub.3 H.sub.7                                                                   CH.sub.2 CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                   5-iodo-1-isopropyl//                                                           propionic acid             36   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            ##STR21##                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CH(CH.sub.3)CO                                                                      C.sub.2 H.sub.5                                                                    ##STR22##                 37   H    H  H    H   6-OH  O n-C.sub.3 H.sub.7                                                                   CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                                            C.sub.2 H.sub.5                                                                   β,β-diethyl-                                                         7-hydroxy-                                                                     1-propyl//propionic                                                            acid                       38   CH.sub.3                                                                            H  H    H   7-NO.sub.2                                                                           O                                                                                 ##STR23##                                                                          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                             C.sub.2 H.sub.5                                                                    ##STR24##                 39   H    H  CH.sub.3                                                                            H   5-CH.sub.3                                                                           O                                                                                 ##STR25##                                                                          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                          C.sub.2 H.sub.5                                                                    ##STR26##                 40   CH.sub.3                                                                            H  H    H   H     O CH.sub. 3                                                                           CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                          C.sub.2 H.sub.5                                                                   1,3-dimethyl-α,.                                                         alpha.-                                                                        dipropyl//propionic                                                            acid                       41   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    H     O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                             CH.sub.3                                                                          α,α,β                                                         ,3-tetramethyl-                                                                1,4,4-triethyl//                                                               propionic acid             42   H    H  CH.sub.3                                                                            CH.sub.3                                                                           H     O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 CO                                                                CH.sub.3                                                                          1-ethyl-β,β,                                                         4,4-                                                                           tetramethyl//propionic                                                         T                                                                              acid                       43   H    H  n-C.sub.3 H.sub.7                                                                   H                                                                                   ##STR27##                                                                           O                                                                                 ##STR28##                                                                          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5)CO    CH.sub.3                                                                          1-cyclopentyl-5-                                                               propionoxy-4-propyl-                                                           α,β,β-                                                         triethyl// propionic                                                           acid                       44   n-C.sub.3 H.sub.7                                                                   H  H    H   4-OCH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CH(CH.sub.3)CO                                                                      C.sub.2 H.sub.5                                                                   1,3-dipropyl-5-methoxy                                                         -                                                                              α-methyl//propio                                                         nic                                                                            acid                       45   C.sub.2 H.sub.5                                                                     H  H    H   5-NO.sub.2                                                                           O CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5).sub.2 CO                                                                            C.sub.2 H.sub.5                                                                   1-methyl-6-nitro-.alph                                                         a.,α,-                                                                   β,β,3-pentae                                                         thyl//                                                                         propionic acid             46   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H   4-C.sub.2 H.sub.5                                                                    O n-C.sub.3 H.sub.7                                                                   CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                             CH.sub.3                                                                          β,1-dipropyl-3,3,                                                         5-                                                                             triethyl//propionic                                                            acid                       47   H    H  H    H   6-OC.sub.2 H.sub.5                                                                   O                                                                                 ##STR29##                                                                          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)C                                        O             C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,                                                         β- diethyl-7-etho                                                         xy// propionic acid        48   H    H  H    H   H     O CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                                C.sub.2 H.sub.5                                                                   1-methyl//butyric                                                              acid,                                                                          m.p. 132                                                                       - 135° C.           49   CH.sub.3                                                                            H  H    H   H     O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                             C.sub.2 H.sub.5                                                                   γ,3-dimethyl-1-e                                                         thyl//                                                                         butyric acid               50   CH.sub.3                                                                            CH.sub.3                                                                          H    H   H     O n-C.sub.3 H.sub.7                                                                   C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                              CH.sub.2 CO   C.sub.2 H.sub.5                                                                   γ,γ-diethy                                                         l-3,3-                                                                         dimethyl-1-propyl//                                                            butyric acid               51   CH.sub.3                                                                            CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                   H   H     O                                                                                 ##STR30##                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-                                               C.sub.3 H.sub.7)CH.sub.2 CO                                                                  C.sub.2                                                                           1-cyclobutyl-3,3-                                                              dimethyl-β,.gamma                                                         .,γ,4-                                                                   tetrapropyl//butyric                                                           acid                       52   H    H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    6-Cl  O CH.sub.3                                                                             ##STR31##    C.sub.2 H.sub.5                                                                   7-chloro-α,.beta                                                         .,β,γ,.gamm                                                         a.,4,4- heptaethyl-1-m                                                         ethyl// butyric acid       53   H    H  CH.sub.3                                                                            H   4-CH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                                C.sub.2 H.sub.5                                                                   1-ethyl-α,.alpha                                                         .,β,β,.gamma                                                         .,γ,4,-                                                                  4,5-octamethyl//                                                               butyric acid               54   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     H                                                                                   ##STR32##                                                                           O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)]                                        .sub.2 CO     C.sub.2 H.sub.5                                                                   6-acetoxy-α,.alp                                                         ha.,β,β,.gam                                                         ma.,3,- 3,4-octaethyl-                                                         1-propyl// butyric                                                             acid                       55   H    H  CH.sub.3                                                                            CH.sub.3                                                                           7-OCH.sub.3                                                                          O                                                                                 ##STR33##                                                                          CH.sub.2 [C(CH.sub.3).sub.3 ] .sub.2                                           CO            C.sub.2 H.sub.5                                                                   1-cyclobutyl-α,.                                                         alpha.,β,β,-                                                          4,4-hexamethyl-8-                                                             methoxy//butyric                                                               acid                       56   H    H  H    H   4-Br  O                                                                                 ##STR34##                                                                          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                         CO            C.sub.2 H.sub.5                                                                   5-bromo-1-cyclopentyl-                                                          α,α,.beta                                                         .-trimethyl// butyric                                                          acid                       57   CH.sub.3                                                                            CH.sub.3                                                                          H    H   4-n-C.sub.3 H.sub.7                                                                  O                                                                                 ##STR35##                                                                          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).su                                        b.2 CO        C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,                                                         α- diethyl-3,3-d                                                         imethyl-                                                                       5-propyl//butyric                                                              acid                       58   H    H  H    H   7-C.sub.2 H.sub.5                                                                    O C.sub.2 H.sub.5                                                                     CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                             C.sub.2 H.sub.5                                                                   1,8-diethyl-α-me                                                         thyl//                                                                         butyric acid               59   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            H   5-F   O n-C.sub.4 H.sub.9                                                                   [CH(CH.sub.3)].sub.3 CO                                                                      C.sub.2 H.sub.5                                                                   1-butyl-6-fluoro-.alph                                                         a.,β,-                                                                    γ,3,3,4-hexameth                                                         yl//                                                                           butyric acid               60   CH.sub.3                                                                            CH.sub.3                                                                          H    H   4-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5)CO    C.sub.2 H.sub.5                                                                   α,γ-diethy                                                         l-1-propyl-                                                                    3,3,5-trimethyl//                                                              butyric acid               61   C.sub.2 H.sub.5                                                                     H  H    H   6-NO.sub.2                                                                           O n-C.sub.4 H.sub.9                                                                   [C(CH.sub.3).sub.2 ].sub.3 CO                                                                C.sub.2 H.sub.5                                                                   1-butyl-3-ethyl-7-                                                             nitro-α,β,.                                                         gamma.-                                                                        trimethyl//butyric                                                             acid                       62   CH.sub.3                                                                            CH.sub.3                                                                          H    H   4-n-C.sub.3 H.sub.7                                                                  O n-C.sub.3 H.sub.7                                                                   CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                           CO            C.sub.2 H.sub.5                                                                   α,β-diethyl                                                         -3,3-                                                                          dimethyl-1,5-dipropyl/                                                         /                                                                              butyric acid               63   H    H  H    H   7-OH  O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2                                                     C(CH.sub.3).sub.2 CO                                                                         C.sub.2 H.sub.5                                                                   1-ethyl-8-hydroxy-                                                             α,α,.gamma                                                         .,γ-tetramethyl/                                                         /                                                                              butyric acid               64   CH.sub.3                                                                            H  CH.sub.3                                                                            H   4-OC.sub.2 H.sub.5                                                                   O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                                C.sub.2 H.sub.5                                                                   5-ethoxy-1-ethyl-.alph                                                         a.,α,-                                                                   β,β,γ,                                                         γ,3,4-                                                                   octomethyl//butyric                                                            acid                       __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________                               Ketoester of           Product: [(Prefix                                       Formula VI             Listed Below)-1,3,4,9-         Starting Material of  Formula II                                                                         ##STR36##             Tetrahydrothiopyrano-                                                          [3,4-b]indole-1- (Suffix                                                       Listed Below)]                Ex.                                                                               R.sup.2                                                                            R.sup.3                                                                           R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                              X R.sup.1                                                                             Alk.sup.1CO    R.sup.19                                                                          Prefix//Suffix                __________________________________________________________________________     65 H   H  H   H   H     S CH.sub.3                                                                            CO             C.sub.2 H.sub.5                                                                   1-methyl//carboxylic                                                           acid                          66 CH.sub.3                                                                           H  H   H   H     S C.sub.2 H.sub.5                                                                     CO             C.sub.2 H.sub.5                                                                   1-ethyl-3-methyl//                                                             carboxylic acid               67 i-C.sub.3 H.sub.7                                                                  H  H   H   5-CH.sub.3                                                                           S i-C.sub.3 H.sub.7                                                                   CO             CH.sub.3                                                                          1,3-diisopropyl-6                                                              methyl//carboxylic                                                             acid                          68 CH.sub.3                                                                           CH.sub.3                                                                          H   H   5-OH  S CH.sub.3                                                                            CO             CH.sub.3                                                                          1,3,3-trimethyl-6-                                                             hydroxy-1-(1-propyl)//                                                         carboxylic acid               69 H   H  H   H   7-C.sub.2 H.sub.5                                                                    S n-C.sub.3 H.sub.7                                                                   CO             CH.sub.3                                                                           8-ethyl-1-propyl//                                                            carboxylic acid               70 H   H  i-C.sub.3 H.sub.7                                                                  H   H     S                                                                                 ##STR37##                                                                          CO             CH.sub.3                                                                          1-cyclopropyl-4-                                                               isopropyl//carboxylic                                                          acid                          71 CH.sub.3                                                                           CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H     S                                                                                 ##STR38##                                                                          CO             CH.sub.3                                                                          1-cyclopentyl-4,4-                                                             diethyl-3,3-dimethyl//                                                         carboxylic acid               72 H   H  CH.sub.3                                                                           H   H     S CH.sub.3                                                                            CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1,4-dimethyl//acetic                                                           acid                          73 H   H  H   H   H     S C.sub.2 H.sub.5                                                                     CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-ethyl//acetic acid,                                                          m.p. 138° C.           74 H   H  H   H   H     S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-propyl//acetic acid,                                                         m.p. 127 - 129°                                                         C.                            75 H   H  H   H   H     S i-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-isopropyl//acetic                                                            acid                          76 CH.sub.3                                                                           H  H   H   H     S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   3-methyl-1-propyl//                                                            acetic acid                   77 CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           H     S C.sub.2 H.sub. 5                                                                    CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1,4-diethyl-3-methyl//                                                         acetic acid                   78 H   H  H   H   H     S CH.sub.3                                                                            CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   α,1-dimethyl//aceti                                                      c acid                        79 H   H  H   H   H     S                                                                                 ##STR39##                                                                          C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-cyclohexyl-α,.alp                                                      ha.- dimethyl//acetic                                                          acid                          80 H   H  H   H   H     S t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-t-butyl//acetic acid        81 H   H  H   H   H     S n-C.sub.4 H.sub.9                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   1-butyl//acetic acid          82 H   H  H   H   7-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   8-methyl-1-propyl//                                                            acetic acid                   83 H   H  H   H   5-Br  S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-bromo-1-propyl//                                                             acetic acid                   84 H   H  H   H   5-OCH.sub.3                                                                          S CH.sub.3                                                                            CH.sub.2 CO    CH.sub.3                                                                          6-methoxy-1-methyl//                                                           acetic acid                   85 H   H  H   H   5-OCOCH.sub.3                                                                        S CH.sub.3                                                                            CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-acetoxy-1-methyl//                                                           acetic acid                   86 H   H  H   H   5-benzyl- oxy                                                                        S CH.sub.3                                                                            CH.sub.2 CO    C.sub.2 H.sub.5                                                                   6-benzyloxy-1-methyl//                                                         acetic acid                   87 H   H  H   H   4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   5-methyl-1-propyl//                                                            acetic acid                   88 H   H  H   H   6-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO    C.sub.2 H.sub.5                                                                   7-methyl-1-propyl//                                                            acetic acid                   89 H   H  H   H   7-F   S CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                   α,α-diethyl-8                                                      -fluoro-1- methyl//acetic                                                       acid                         90 CH.sub.3                                                                           CH.sub.3                                                                          H   H   5-Cl  S n-C.sub.3 H.sub.7                                                                   CH(iC.sub.3 H.sub.7)CO                                                                        C.sub.2 H.sub.5                                                                   6-chloro-3,3-dimethyl-                                                         α-isopropyl-1-                                                           propyl//acetic acid           91 CH.sub.3                                                                           CH.sub.3                                                                          H   H   5-OC.sub.2 H.sub.5                                                                   S                                                                                 ##STR40##                                                                          CH(C.sub.2 H.sub.5)CO                                                                         C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.al                                                      pha.- diethyl-3,3-                                                             dimethyl-6-ethoxy//                                                            acetic acid                   92 CH.sub.3                                                                           CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-C.sub.2 H.sub.5                                                                    S                                                                                 ##STR41##                                                                          C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                    1-cyclohexyl-α,.al                                                      pha.,3,3- tetramethyl-4,4                                                      ,7- triethyl//acetic                                                           acid                          93 CH.sub.3                                                                           H  n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                  S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CO C.sub.2 H.sub.5                                                                   α,3-dimethyl-1-ethy                                                      l                                                                              4,4,5-tripropyl//                                                              acetic acid                   94 H   H  H   H   H     S n-C.sub.3 H.sub.7                                                                   C(CH.sub.3).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   α,α-dimethyl-                                                      1- propyl//acetic acid        95 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                    S t-C.sub.4 H.sub.9                                                                   C(i-C.sub.3 H.sub.7).sub.2 CO                                                                 C.sub.2 H.sub.5                                                                   1-t-butyl-α,α                                                      - diisopropyl-3,3,4,4-                                                         5-pentaethyl//acetic                                                           acid                          96 H   H  H   H   H     S CH.sub.3                                                                            CH.sub.2 CH.sub.2 CO                                                                          C.sub.2 H.sub.5                                                                   1-methyl// propionic                                                           acid                          97 CH.sub.3                                                                           CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3                                                                            ##STR42##                                                                           S C.sub.2 H.sub.5                                                                     CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                   8-acetoxy-1-ethyl-                                                             α,3,3,4,4-                                                               pentamethyl// propionic                                                        acid                          98 H   H  H   H   6-OH  S n-C.sub.3 H.sub. 7                                                                  CH.sub.2 C(C.sub.2 H.sub.5).sub.2 CO                                                          C.sub.2 H.sub.5                                                                   β,β-diethyl-7-                                                       ydroxy-1-propyl//                                                              propionic acid                99 CH.sub.3                                                                           H  H   H   7-NO.sub.2                                                                           S                                                                                 ##STR43##                                                                          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                   1-cyclobutyl-3- methyl-8-                                                      nitro-α- propyl//pr                                                      opionic acid                  100                                                                               H   H  CH.sub.3                                                                           H   5-CH.sub.3                                                                           S                                                                                 ##STR44##                                                                          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                   1,cyclopropyl-α,.al                                                      pha.ββ                                                               4,6-hexamethyl//                                                               propionic acid                101                                                                               CH.sub.3                                                                           H  H   H   H     S CH.sub.3                                                                            CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                           C.sub.2 H.sub.5                                                                   1,3-dimethyl-α,.alp                                                      ha.-                                                                           dipropyl//propionic                                                            acid                          102                                                                               CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H     S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                              CH.sub.3                                                                          1,4,4-triethyl-α,.a                                                      lpha.,β,-                                                                 3-tetramethyl                                                                  propionic acid                103                                                                               H   H  CH.sub.3                                                                           CH.sub.3                                                                           H     S C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 CO                                                                 CH.sub.3                                                                          1-ethyl-β,β,4,4                                                      -                                                                              tetramethyl//                                                                  propionic acid                104                                                                               H   H  n-C.sub.3 H.sub.7                                                                  H                                                                                   ##STR45##                                                                           S                                                                                 ##STR46##                                                                          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5)CO     CH.sub.3                                                                          1-cyclopentyl-5-                                                               propionoxy-4-propyl-                                                           α,β,                                                                -triethyl// propionic                                                          acid                          105                                                                               n-C.sub.3 H.sub.7                                                                  H  H   H   4-OCH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CH(CH.sub.3)CO                                                                       C.sub.2 H.sub.5                                                                   1,3-dipropyl-5-                                                                methoxy-α-methyl//                                                       y                                                                              propionic acid                106                                                                               C.sub.2 H.sub.5                                                                    H  H   H   5-NO.sub.2                                                                           S CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5).sub.2 CO                                                                             C.sub.2 H.sub.5                                                                   1-methyl-6-nitro-                                                              α,α,β,.b                                                      eta.,3-pentaethyl//                                                            propionic acid                107                                                                               C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H   H   4-C.sub.2 H.sub.5                                                                    S n-C.sub.3 H.sub.7                                                                   CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                              CH.sub.3                                                                          β,1-dipropyl-3,3,5-                                                       5                                                                              triethyl//propionic                                                            acid                          108                                                                               H   H  H   H   6-OC.sub.2 H.sub.5                                                                   S                                                                                 ##STR47##                                                                          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                      C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.be                                                      ta.- diethyl-7-ethoxy//                                                        propionic acid                109                                                                               H   H  H   H   H     S CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                                 C.sub.2 H.sub.5                                                                   1-methyl//butyric acid        110                                                                               CH.sub.3                                                                           H  H   H   H     S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                   γ,3-dimethyl-1-ethy                                                      l//                                                                            butyric acid                  111                                                                               CH.sub.3                                                                           CH.sub.3                                                                          H   H   H     S n-C.sub.3 H.sub.7                                                                   C(C.sub.2 H.sub.5).sub.2 CH.sub.2 CH.sub.2                                     CO             C.sub.2 H.sub.5                                                                   γ,γ-diethyl-3                                                      ,3-                                                                            dimethyl-1-propyl//                                                            butyric acid                  112                                                                               CH.sub.3                                                                           CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                  H   H     S                                                                                 ##STR48##                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                        H.sub.7 CH.sub.2 CO                                                                           C.sub.2 H.sub.5                                                                   1-cyclobutyl-3,3-                                                              dimethyl-β,γ,.                                                      gamma.,4- tetrapropyl//                                                        butyric acid                  113                                                                               H   H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-Cl  S CH.sub.3                                                                            [C(C.sub.2 H.sub.5).sub.2 ].sub.2 CH(C.sub.                                    2 H.sub.5)CO   C.sub.2 H.sub.5                                                                   7-chloro-α,β,.                                                      beta. ,γ,γ,                                                        4,4-heptaethyl-1-                                                              methyl//butyric acid          114                                                                               H   H  CH.sub.3                                                                           H   4-CH.sub.3                                                                           S C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 O                                                                  C.sub.2 H.sub.5                                                                   1-ethyl-α,α,.                                                      beta.,β,γ,.gam                                                      ma.,                                                                           4,5-octamethyl//                                                               butyric acid                  115                                                                               C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    H                                                                                   ##STR49##                                                                           S n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)].sub                                    .2 CO          C.sub.2 H.sub.5                                                                   6-acetoxy-α,α                                                      ,β,β, γ,3                                                      ,3,4-octaethyl- propyl//b                                                      utyric acid                   116                                                                               H   H  CH.sub.3                                                                           CH.sub.3                                                                           7-OCH.sub.3                                                                          S                                                                                 ##STR50##                                                                          CH.sub.2 [C(CH.sub.3).sub.3 ].sub.2                                                           C.sub.2 H.sub.5                                                                   1-cyclobutyl-α,.alp                                                      ha.,β, β,4,4-he                                                      xamethyl-8- methoxy//buty                                                      ric acid                      117                                                                               H   H  H   H   4-Br  S                                                                                 ##STR51##                                                                          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                   5-bromo-1-cyclopentyl                                                          α,α,β-tr                                                      imethyl// butyric acid        118                                                                               CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                  S                                                                                 ##STR52##                                                                          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                     CO             C.sub.2 H.sub.5                                                                   1-cyclopropyl-α,.al                                                      pha., diethyl-3,3-dimethy                                                      l- 5-propyl//butyric                                                           acid                          119                                                                               H   H  H   H   7-C.sub.2 H.sub.5                                                                    S C.sub.2 H.sub.5                                                                     CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                              C.sub.2 H.sub.5                                                                   1,8-diethyl-α-                                                           methyl//butyric acid          120                                                                               CH.sub.3                                                                           CH.sub.3                                                                          CH.sub.3                                                                           H   5-F   S n-C.sub.4 H.sub.9                                                                   [CH(CH.sub.3)].sub.3 CO                                                                       C.sub.2 H.sub.5                                                                   1-butyl-6-fluoro-                                                              α,β,γ,3,                                                      3,4-                                                                           hexamethyl//butyric                                                            acid                          121                                                                               CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5)CO     C.sub.2 H.sub.5                                                                   α,γ-diethyl-1                                                      -                                                                              propyl-3,3,5-trimethyl                                                         butyric acid                  122                                                                               C.sub.2 H.sub.5                                                                    H  H   H   6-NO.sub.2                                                                           S n-C.sub.4 H.sub.9                                                                   [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                   1-butyl-3-ethyl-7-                                                             nitro-α,β,.gam                                                      ma.-                                                                           trimethyl//butyric                                                             acid                          123                                                                               CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                  S n-C.sub.3 H.sub.7                                                                   CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                          C.sub.2 H.sub.5                                                                   α,β-diethyl-                                                        3,3-dimethyl-1,5-                                                              dipropyl//butyric                                                              acid                          124                                                                               H   H  H   H   7-OH  S C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).sub.                                    2 CO           C.sub.2 H.sub.5                                                                   1-ethyl-8-hydroxy-                                                             α,α,γ,.                                                      gamma.-tetramethyl//                                                           butyric acid                  125                                                                               CH.sub.3                                                                           H  CH.sub.3                                                                           H   4-OC.sub.2 H.sub.5                                                                   S C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                                 C.sub.2 H.sub.5                                                                   5-ethoxy-1-ethyl-                                                              α,α,β,.b                                                      eta.,γ,γ,3,4-                                                      N                                                                              octomethyl//butyric                                                            acid                          __________________________________________________________________________

EXAMPLE 126 N,N,1-TRIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETAMIDE[VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O AND Z = CH₂ CON(CH₃)₂ ]

To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5° C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149° - 151° C., ν_(max) ^(CHCl).sbsp.3 3375, 1634 cm⁻¹.

In the same manner but replacing the 40% aqueous solution of dimethylamine with an equivalent amount of ammonium hydroxide (concentrated), methylamine (30% aqueous solution), n-hexylamine (20% aqueous solution), diethylamine (30% aqueous solution), isopropylamine (40% aqueous solution), ethylamine (70% aqueous solution), pyrrolidone (50% aqueous solution), piperidine, morpholine, N-methylpiperazine,

1-methyl-1,3,4,9-tetrahydropyran[3,4-b]indole-1-acetamide, m.p. 158° - 160° C.,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 138° - 140° C.,

N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 99° C.,

N-isipropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 151° - 153° C.,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 152° - 153° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]pyrrolidine, m.p. 119° - 120° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]piperidine, m.p. 148° - 149° C.,

1[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]morpholine, m.p. 141° - 142° C., and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]piperazine, are obtained respectively.

By following the procedure of Example 126 but using as starting material an equivalent amount of one of the acid compounds of formula VII, described in Examples 2 to 125, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine described in Example 126, then the corresponding amide compound of formula VII is obtained. Examples of such amides are listed as products in Tables III, IV, V and VI together with the appropriate starting material and amine used for the preparation of the amide. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE III                                    __________________________________________________________________________            NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW)-                          IN WHICH STARTING    1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                               PREPARED      AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________     127    2             CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//propionamide,                                                    m.p. 149 - 150° C.                          128    2             NH.sub.3                                                                              1-methyl//propionamide                             129    2             (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//propionamide                      130    2             n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//propionamide                     131    2             (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//propionamide                 132    4             CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//carboxamide                          133    4             NH.sub.3                                                                              1-methyl//carboxamide, m.p. 188 -                                              189° C.                                     134    4             (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//carboxamide                       135    4             n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//carboxamide                      136    4             C.sub.2 H.sub.5 NH.sub.2                                                              N-ethyl-1-methyl//carboxamide                      137    5             CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-ethyl//carboxamide                  138    9             (CH.sub.3).sub.2 NH                                                                   1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                                139    11            (CH.sub.3).sub.2 NH                                                                   N,N,1,4-tetramethyl//acetamide                     140    12            CH.sub.3 NH.sub.2                                                                     1-ethyl-N-methyl//acetamide                        141    12            NH.sub.3                                                                              1-ethyl//acetamide                                 142    12            (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-ethyl//acetamide                    143    12            n-C.sub.16 H.sub.13 NH.sub.2                                                          1-ethyl-N-hexyl//acetamide                         144    12            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N,1-triethyl//acetamide                          145    13            CH.sub.3 NH.sub.2                                                                     N-methyl-1-propyl//acetamide                       146    13            NH.sub.3                                                                              1-propyl//acetamide                                147    13            (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-propyl//acetamide,                                              m.p. 159 - 162° C.                          148    13            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-propyl//acetamide                        149    13            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-propyl//acetamide                    150    14            CH.sub.3 NH.sub.2                                                                     1-isopropyl-N-methyl//acetamide                    151    14            NH.sub.3                                                                              1-isopropyl//acetamide                             152    14            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-isopropyl//acetamide                 153    15            CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-propyl//acetamide                   154    15            (CH.sub.3).sub.2 NH                                                                   1-propyl-N,N,3-trimethyl//                                                     acetamide                                          155    15            n-C.sub.6 H.sub.13 NH.sub.2                                                           n-hexyl-3-methyl-1-propyl//                                                    acetamide                                          156    15            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                          157    17            CH.sub.3 NH.sub.2                                                                     N,α,1-trimethyl//acetamide                   158    17            NH.sub.3                                                                              α,1-dimethyl//acetamide                      159    17            (CH.sub.3).sub.2 NH                                                                   N,N,α,1-tetramethyl//acetamide               160    17            n-C.sub.6 H.sub.13 NH.sub.2                                                           α,1-dimethyl-N-hexyl//acetamide              161    17            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-α,1-dimethyl//                                               acetamide                                          162    18            CH.sub.3 NH.sub.2                                                                     1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                          163    21            CH.sub.3 NH.sub.2                                                                     N,8-dimethyl-1-propyl//acetamide                   164    25            NH.sub.2                                                                              6-benzyloxy-1-methyl//acetamide                    165    26            (CH.sub.3).sub.2 NH                                                                   1-propyl-N,N,5-trimethyl//                                                     acetamide                                          166    30            n-C.sub.6 H.sub.13 NH.sub.2                                                           1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                          167    35            CH.sub.3 NH.sub.2                                                                     5-iodo-1-isopropyl-N-methyl//                                                  propionamide                                       168    38            NH.sub.2                                                                              1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                       169    41            (CH.sub.3).sub.2 NH                                                                   N,N,α,α,β,3-hexamethyl-1,4,4-                                 N                                                                              triethyl//propionamide                             170    44            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1,3-dipropyl-5-                                                    methoxy-α-methyl//propionamide               171    46            CH.sub.3 NH.sub.2                                                                     N-methyl-β,1-dipropyl-3,3,5-                                              triethyl//propionamide                             172    48            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//butyramide                        173    48            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//butyramide                           174    48            NH.sub.2                                                                              1-methyl//butyramide                               175    48            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//butyramide                       176    51            CH.sub.3 NH.sub.2                                                                     1-cyclobutyl-β,γ,γ,4-tetrapro                                 pyl-                                                                           N,3,3-trimethyl//butyramide                        177    53            (CH.sub.3).sub.2 NH                                                                   N,N,α,α,β,β,γ,.gam                                 ma.,4,5-decamethyl-                                                            1-ethyl//butyramide                                178    56            NH.sub.2                                                                              5-bromo-1-cyclopentyl-α,α,β-                                  o                                                                              trimethyl//butyramide                              179    58            CH.sub.3 NH.sub.2                                                                     1,8-diethyl-N,α-dimethyl//                                               butyramide                                         180    60            (C.sub.2 H.sub.5).sub.2 NH                                                            1-propyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                        181    62            n-C.sub.6 H.sub. 13 NH.sub.2                                                          α,β-diethyl-3,3-dimethyl-                                           1,5-dipropyl-N-hexyl//butyramide                   __________________________________________________________________________

                                      TABLE IV                                     __________________________________________________________________________            NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW)-                          IN WHICH STARTING    1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                               PREPARED      AMINE  PREFIX//SUFFIX                                     __________________________________________________________________________     182    2             pyrrolidine                                                                           1-[(1-methyl//propionyl]pyrrolidine                183    2             piperidine                                                                            1-[(1-methyl//propionyl]piperidine                 184    2             morpholine                                                                            4-[(1-methyl//propionyl]morpholine                 185    2             piperazine                                                                            1-[(1-methyl//propionyl]piperazine                 186    2             N-methyl-                                                                             1-methyl-4-[1-methyl//propionyl]-                                       piperazine                                                                            piperazine                                         187    2             N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                       ethanol                                                                               propionyl]piperazine                               188    4             pyrrolidine                                                                           1-[(1-methyl//carbonyl]pyrrolidine                 189    4             morpholine                                                                            4-[(1-methyl//carbonyl]morpholine                  190    5             N-ethyl-                                                                              1-ethyl-4-[(1-ethyl-3-methyl//                                          piperazine                                                                            carbonyl]piperazine                                191    11            piperidine                                                                            1-[(1,4-dimethyl//acetyl]-                                                     piperidine                                         192    12            morpholine                                                                            4-[(1-ethyl//acetyl]morpholine                     193    12            N-piperazine-                                                                         1-(3-hydroxypropyl)-4-                                                  propanol                                                                              [(1-ethyl//acetyl]piperazine                       194    13            pyrrolidine                                                                           1-[(1-propyl//acetyl]pyrrolidine                   195    13            morpholine                                                                            4-[(1-propyl//acetyl]morpholine                    196    14            piperidine                                                                            1-[(1-isopropyl//acetyl]piperidine                 197    15            piperazine                                                                            1-[(3-methyl-1-propyl//acetyl]-                                                piperazine                                         198    17            N-ethyl-                                                                              1-ethyl-4-[(α,1-dimethyl//acetyl]-                                piperazine                                                                            piperazine                                         199    25            pyrrolidine                                                                           1-[(6-benzyloxyl-1-methyl//acetyl]-                                            pyrrolidine                                        200    26            piperidine                                                                            1-[(5-methyl-1-propyl//acetyl]                                                 piperidine                                         201    30            morpholine                                                                            4-[(1-cyclopropyl-α,α-diethyl-                                     3,3-dimethyl-6-ethoxy//acetyl]-                                                morpholine                                         202    36            piperazine                                                                            1-[8-acetoxy-1-ethyl-α,3,3,4,4-                                          pentamethyl//propionyl]piperazine                  203    39            N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-cyclo-                                         ethanol                                                                               propyl-α,α,β,β,4,6-hexam                                 ethyl//                                                                        propionyl]piperazine                               204    40            pyrrolidine                                                                           1-[(1,3-dimethyl-α,α-dipropyl//                                    propionyl]pyrrolidine                              205    42            morpholine                                                                            4-[(1-ethyl-β,β,4,4-tetramethyl//                                    propionyl]morpholine                               206    47            N-propyl-                                                                             1-propyl-4-[(1-cyclopropyl-α,β-                              piperazine                                                                            diethyl-6-ethoxy//propionyl]-                                                  piperazine                                         207    48            pyrrolidine                                                                           1-[(1-methyl//butyryl]pyrrolidine                  207a   48            N-piperazine-                                                                         1-(hydroxymethyl)-4-[(1-methyl//                                        methanol                                                                              butyryl]piperazine                                 208    50            piperidine                                                                            1-[γ,γ-diethyl-3,3-dimethyl-1-                                     propyl//butyryl]piperidine                         209    52            morpholine                                                                            4-[(7-chloro-α,β,β,γ,.ga                                 mma.,4,4-                                                                      heptaethyl-1-methyl//butyryl]-                                                 morpholine                                         210    59            piperazine                                                                            1-[(1-butyl-6-fluoro-α,β,γ,3,                                 3,4-                                                                           hexamethyl//butyryl]piperazine                     __________________________________________________________________________

                                      TABLE V                                      __________________________________________________________________________                                 PRODUCT:                                                  NO. OF THE EXAMPLE   [(PREFIX LISTED BELOW)-1,3,4,9-                           IN WHICH STARTING    TETRAHYDROTHIOPYRANO-[3,4-b]-                             MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                               PREPARED        AMINE                                                                                 PREFIX//SUFFIX                                   __________________________________________________________________________     211    3             CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//acetamide                            212    3             NH.sub.2                                                                              1-methyl//acetamide                                213    3             n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//acetamide                        214    3             (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//acetamide,                                                    m.p. 182° C.                                215    3             (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//acetamide                    216    96            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//propionamide                         217    96            NH.sub.3                                                                              1-methyl//propionamide                             218    96            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//propionamide                      219    96            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//propionamide                     220    96            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//propion-                                                 amide                                              221    65            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//carboxamide                          222    65            NH.sub.3                                                                              1-methyl//carboxamide                              223    65            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//carboxamide                       224    65            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//carboxamide                      225    65            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//carboxamide                  226    66            CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-ethyl//carboxamide                  227    69            NH.sub.3                                                                              8-ethyl-1-propyl//carboxamide                      228    70            (CH.sub.3).sub.2 NH                                                                   1-cyclopropyl-N,N-dimethyl-4-                                                  isopropyl//carboxamide                             229    72            (CH.sub.3).sub.2 NH                                                                   N,N,1,4-tetramethyl//acetamide                     230    73            CH.sub.3 NH.sub.2                                                                     1-ethyl-N-methyl//acetamide                        231    73            NH.sub.3                                                                              1-ethyl//acetamide                                 232    73            (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-ethyl//acetamide                    233    73            n-C.sub.16 H.sub.13 NH.sub.2                                                          1-ethyl-N-hexyl//acetamide                         234    73            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N,1-triethyl//acetamide                          235    74            CH.sub.3 NH.sub.2                                                                     N-methyl-1-propyl//acetamide                       236    74            NH.sub.3                                                                              1-propyl//acetamide                                237    74            (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-propyl//acetamide                   238    74            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-propyl//acetamide                        239    74            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-propyl//acetamide                    240    75            CH.sub.3 NH.sub.2                                                                     1-isopropyl-N-methyl//acetamide                    241    75            NH.sub.3                                                                              1-isopropyl//acetamide                             242    75            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-isopropyl//acetamide                 243    76            CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-propyl//acetamide                   244    76            NH.sub.3                                                                              3,methyl-1-propyl//acetamide                       245    76            (CH.sub.3).sub.2 NH                                                                   1-propyl,N,N,3-trimethyl//                                                     acetamide                                          246    76            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-3-methyl-1-propyl//                                                    acetamide                                          247    76            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                          248    78            CH.sub.3 NH.sub.2                                                                     N,α,1-trimethyl//acetamide                   249    78            NH.sub.3                                                                              α,1-dimethyl//acetamide                      250    78            (CH.sub.3).sub.2 NH                                                                   N,N,α,1-tetramethyl//acetamide               251    78            n-C.sub.6 H.sub.13 NH.sub.2                                                           α,1-dimethyl-N-hexyl//acetamide              252    78            (C.sub.2 H.sub. 5).sub.2 NH                                                           N,N-diethyl-α,1-dimethyl//                                               acetamide                                          253    79            CH.sub.3 NH.sub.2                                                                     1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                          254    82            CH.sub.3 NH.sub.2                                                                     N,8-dimethyl-1-propyl//acetamide                   255    83            NH.sub.2                                                                              6-bromo-1-propyl//acetamide                        256    89            (CH.sub.3).sub.2 NH                                                                   α,α-diethyl-8-fluoro-N,N,1-                                        trimethyl//acetamide                               257    91            n-C.sub.6 H.sub.13 NH.sub.2                                                           1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                          258    99            NH.sub.2                                                                              1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                       259    102           (CH.sub.3).sub.2 NH                                                                   N,N,α,α,β,3-hexamethyl-1,4,4-                                 N                                                                              triethyl//propionamide                             260    105           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1,3-dipropyl-5-                                                    methoxy-α-methyl//propionamide               261    107           CH.sub.3 NH.sub.2                                                                     β,1-dipropyl-N-methyl-3,3,5-                                              triethyl//propionamide                             262    108           CH.sub.3 NH.sub.2                                                                     1-cyclopropyl-α,β-diethyl-6-                                        ethoxy-N-methyl//propionamide                      263    109           (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//butyramide                        264    109           CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//butyramide                           265    109           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//butyramide                       266    112           CH.sub.3 NH.sub.2                                                                     1-cyclobutyl-β,γ,γ,4-tetrapro                                 pyl-                                                                           N,3,3-trimethyl//butyramide                        267    113           (CH.sub.3).sub.2 NH                                                                   7-chloro-α,β,β,γ,γ                                 ,4,4-heptaethyl-                                                               N,N,1-trimethyl//butyramide                        268    117           NH.sub.2                                                                              5-bromo-1-cyclopentyl-α,α,β-                                  O                                                                              trimethyl//butyramide                              269    119           CH.sub.3 NH.sub.2                                                                     1,8-diethyl-N,α-dimethyl//                                               butyramide                                         270    121           (C.sub.2 H.sub.5).sub.2 NH                                                            1-propyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                        271    123           n-C.sub.6 H.sub.13 NH.sub.2                                                           α,β-diethyl-3,3-dimethyl-1,5-                                       dipropyl-N-hexyl//butyramide                       __________________________________________________________________________

                                      TABLE VI                                     __________________________________________________________________________                                 PRODUCT: [(PREFIX LISTED BELOW)-                          NO. OF THE EXAMPLE   1,3,4,9-TETRAHYDROTHIOPYRANO-                             IN WHICH STARTING    [3,4-b]INDOLE-1-(SUFFIX LISTED                            MATERIAL IS          BELOW]                                             EXAMPLE                                                                               PREPARED       AMINE   PREFIX//SUFFIX                                   __________________________________________________________________________     272    3             pyrrolidine                                                                           1-[(1-methyl//acetyl]pyrrolidine                   273    3             piperidine                                                                            1-[(1-methyl//acetyl]piperidine                    274    3             morpholine                                                                            4-[(1-methyl//acetyl]morpholine                    275    3             piperazine                                                                            1-[(1-methyl//acetyl]piperazine                    276    3             N-methyl-                                                                             1-methyl-4-[1-methyl//acetyl]-                                          piperazine                                                                            piperazine                                         277    3             N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                       ethanol                                                                               acetyl]piperazine                                  278    96            pyrrolidine                                                                           1-[(1-methyl//propionyl]-                                                      pyrrolidine                                        279    96            piperidine                                                                            1-[(1-methyl//propionyl]piperidine                 280    96            morpholine                                                                            4-[(1-methyl//propionyl]morpholine                 281    96            piperazine                                                                            1-[(1-methyl//propionyl]piperazine                 282    96            N-methyl-                                                                             1-methyl-4-[1-methyl//propionyl]-                                       piperazine                                                                            piperazine                                         283    96            N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-methyl//                                       ethanol                                                                               propionyl]piperazine                               284    65            pyrrolidine                                                                           1-[(1-methyl//carbonyl]pyrrolidine                 285    65            morpholine                                                                            4-[(1-methyl//carbonyl]morpholine                  286    66            N-ethyl-                                                                              1-ethyl-4-[(1-ethyl-3-methyl//                                          piperazine                                                                            carbonyl]piperzine                                 287    72            piperidine                                                                            1-[(1,4-dimethyl//acetyl]-                                                     piperidine                                         288    73            morpholine                                                                            4-[(1-ethyl//acetyl]morpholine                     289    73            N-piperazine-                                                                         1-(3-hydroxypropyl)-4-[(1-ethyl//                                       propanol                                                                              acetyl]piperazine                                  290    74            pyrrolidine                                                                           1-[(1-propyl//acetyl]pyrrolidine                   291    74            morpholine                                                                            4-[ (1-propyl//acetyl]morpholine                   292    75            piperidine                                                                            1-[(1-isopropyl//acetyl]piperidine                 293    76            piperazine                                                                            1-[(3-methyl-1-propyl//acetyl]-                                                piperazine                                         294    78            N-ethyl-                                                                              1-ethyl-4-[(α,1-dimethyl//acetyl]-                                piperazine                                                                            piperazine                                         295    86            pyrrolidine                                                                           1-[(6-benzyloxyl-1-methyl//                                                    acetyl]pyrrolidine                                 296    87            piperidine                                                                            1-[(5-methyl-1-propyl//acetyl]-                                                piperidine                                         298    91            morpholine                                                                            4-[(1-cyclopropyl-α,α-diethyl-                                     3,3-dimethyl-6-ethoxy//acetyl]-                                                morpholine                                         299    97            piperazine                                                                            1-[(8-acetoxy-1-ethyl-α,3,3,4,4-                                         pentamethyl//propionyl]piperazine                  300    100           N-piperazine-                                                                         1-(2-hydroxyethyl)-4-[(1-cyclo-                                         ethanol                                                                               propyl-α,α,β,β,4,6-hexam                                 ethyl//                                                                        propionyl]piperazine                               301    101           pyrrolidine                                                                           1-[(1,3-dimethyl-α,α-dipropyl//                                    propionyl]pyrrolidine                              302    103           morpholine                                                                            4-[(1-ethyl-β,β,4,4-tetramethyl//                                    propionyl]morpholine                               303    108           N-propyl-                                                                             1-propyl-4-[(1-cyclopropyl-α,β-                              piperazine                                                                            diethyl-6-ethoxy//propionyl]-                                                  piperazine                                         304    109           pyrrolidine                                                                           1-[(1-methyl//butyryl]pyrrolidine                  305    109           N-piperazine-                                                                         1-(hydroxymethyl)-4-[(1-methyl//                                        methanol                                                                              butyryl]piperazine                                 306    111           piperidine                                                                            1-[(γ,γ,-diethyl-3,3-dimethyl-1-                                   propyl//butyryl]piperidine                         307    113           morpholine                                                                            4-[(7-chloro-α,β,β,γ,.ga                                 mma.,4,4-                                                                      heptaethyl-1-methyl//butyryl]-                                                 morpholine                                         308    120           piperazine                                                                            1-[(1-butyl-6-fluoro-α,β,γ,3,                                 3,4-                                                                           hexamethyl//butyryl]piperazine                     __________________________________________________________________________

EXAMPLE 309 1-[2-(DIMETHYLAMINO)ETHYL]-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE [I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = 0 Y = CH₂ CH₂ N(CH₃)₂ ]

A solution of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetamide (5.0 g, 0.018 mole), prepared as described in Example 126, is added dropwise to a cooled, well-stirred mixture of lithium aluminum hydride (1.4 g, 0.036 mole) in 200 ml of ether. Stirring is continued for one hour at room temperature, then the mixture is heated under reflux for 2 hr.

After cooling in an ice-water bath, 6.2 ml of water is added dropwise to destroy the excess hydride. Then 100 ml more of water is added and the ether phase decanted. The aqueous phase is extracted once with benzene. The combined organic phases are washed with water, dried over sodium sulfate, and evaporated to dryness to afford 5 g of oil which crystallized on standing. The crystallized product is recrystallized from ether to afford the pure title compound, m.p. 133° - 135° C., nmr(CDCl₃)δ 1.53 (s, 3H), 2.07 (2H), 9.74 (1H), 10.55 (6H).

The corresponding oxalic acid addition salt (oxalate), 1-[(2-dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole oxalate, has m.p. 181° - 183° C. after crystallization from methanol-ether.

In the same manner but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride, the title compound is also obtained.

In the same manner but replacing N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide with an equivalent amount of the following amides described in Example 126,

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]pyrrolidine,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]piperidine,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]morpholine, and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]piperazine, then there are obtained,

1-(2-aminoethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 80° - 84° C., ν_(max) ^(CHCl).sbsp.3 3455, 3280cm⁻¹,

1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano- [3,4-b]indole, m.p. 160° -163° C., (m.p. of corresponding oxalic acid addition salt, 140° - 144° C.),

1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-[2-(diethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano- [3,4-b]indole,

1-[2-(isopropylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-[2-(ethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-methyl-1-[2-(1-pyrrolidinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,

nmr (CDCl₃) δ 1.62 (3H), 2.00 (m, 4H), 4.05 (m, 2H),

m.p. of corresponding maleic acid addition salt (maleate), 192° - 192° C.

1-methyl-1-(2-piperidinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 146° - 148° C., m.p. of corresponding maleic acid addition salt, 147° - 149° C.,

1-methyl-1-(2-morpholinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (DMSO-d₅) δ 1.50 (3H), 6.07 (2H), 6.87 - 7.65 (m, 4H), 10.86 (1H), m.p. of corresponding maleic acid addition salt, 192° - 193° C., and

1-methyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl₃) δ 1.47 (3H), 2.58 (3H), 3.87 (t, 2H), [m.p. of corresponding maleic acid addition salt (i.e. dimaleate), 208° - 210° C.], respectively.

By following the procedure of Example 309 but using as starting material an equivalent amount of one of the amide compounds of formula VII, described in Examples 127 to 308 instead of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, then the corresponding compounds of formula I in which R⁷ is hydrogen are obtained. Examples of such compounds of formula I are listed as products in Tables VII and VIII together with the appropriate starting material, amides of formula VII. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE VII                                    __________________________________________________________________________            NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                            PRODUCT: (PREFIX LISTED BELOW)-                                  MATERIAL IS   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          EXAMPLE                                                                               PREPARED      INDOLE                                                    __________________________________________________________________________     310    127           1-methyl-1-[3-(methylamino)propyl],                                            nmr (CDCl.sub.3) δ1.48 (3H), 1.87 (4H),                                  2.47 (3H), corresponding oxalic                                                acid addition salt has m.p.                                                    110° C.                                            311    128           1-(3-aminopropyl)-1-methyl                                312    129           1-methyl-1-[3-(dimethylamino)-                                                 propyl], m.p. 114 - 116° C.,                                            corresponding oxalic acid                                                      addition salt has m.p. 168 - 172° C.               313    130           1-[3-(hexylamino)propyl]-1-methyl                         314    131           1-[3-(diethylamino)propyl]-1-                                                  methyl                                                    315    132           1-methyl-1-[(methylamino)methyl]                                               CHCl.sub.3                                                316    133           1-(aminomethyl)-1-methyl, δ max                                          3465, 3400, 3180, 2930,                                                        corresponding hydrochloric acid                                                addition salt (hydrochloride)                                                  has m.p. 251 - 252° C.                             317    134           1-[(dimethylamino)methyl]-1-                                                   methyl                                                    318    135           1-[(hexylamino)methyl]-1-methyl                           319    136           1-[(ethylamino)methyl]-1-methyl,                                               nmr (DMSO-d.sub.6) δ1.18 (3H),                                           1.62 (3H), 2.80 (2H); correspond-                                              ing hydrochloric acid addition                                                 salt has m.p. 242 - 243° C.                        320    137           1-ethyl-3-methyl-1-[(methylamino)-                                             methyl]                                                   321    138           1-cyclopropyl-1-[(dimethylamino)-                                              methyl)-4-isopropyl                                       322    139           1,4-dimethyl-1-[2-(dimethylamino)-                                             ethyl]                                                    323    140           1-ethyl-1-[2-(methylamino)ethyl]                          324    141           1-(2-aminoethyl)-1-ethyl                                  325    142           1-[2-(dimethylamino)ethyl]-1-                                                  ethyl                                                     326    143           1-ethyl-1-[2-(hexylamino)ethyl]                           327    144           1-[2-(diethylamino)ethyl]-1-ethyl                         328    145           1-[2-(methylamino)ethyl]-1-propyl                         329    146           1-(aminoethyl)-1-propyl                                   330    147           1-[2-(dimethylamino)ethyl]-1-                                                  propyl, nmr (CDCl.sub.3) 0.84 (t,3H),                                          1.21 (3, 6H), 2.79 (t, 5 = 5.5 cps,                                            2H) corresponding maleic acid                                                  addition salt has m.p. 152 - 154° C)               331    148           1-[2-(hexylamino)ethyl]-1-propyl                          332    149           1-[2-(diethylamino)ethyl]-1-propyl                        333    150           1-isopropyl-1-[2-(methylamino)-                                                ethyl]                                                    334    151           1-(2-aminoethyl)-1-isopropyl                              335    152           1-[2-(diethylamino)ethyl-1-                                                    isopropyl                                                 336    153           3-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                  337    154           1-[2-(dimethylamino)ethyl]-3-                                                  methyl-1-propyl                                           338    155           1-[2-(hexylamino)ethyl]-3-methyl-                                              1-propyl                                                  339    156           1-[2-(diethylamino)ethyl]-3-                                                   methyl-1-propyl                                           340    157           1-[1-methyl-2-(methylamino)ethyl]-                                             1-methyl                                                  341    158           1-(2-amino-1-methyl-ethyl)-1-                                                  methyl                                                    342    159           1-[2-(dimethylamino)-1-methyl-                                                 ethyl]-1-methyl                                           343    160           1-[2-(hexylamino)-1-methyl-ethyl)-                                             1-methyl                                                  344    161           1-[ 2-(diethylamino)-1-methyl-ethyl]-                                          1-methyl                                                  345    162           1-cyclohexyl-1-[1,1-dimethyl-2-                                                (methylamino)ethyl]                                       346    163           8-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                  347    164           1-(2-aminoethyl)-6-benzyloxy-1-                                                methyl                                                    348    165           1-[2-(dimethylamino)ethyl]-5-                                                  methyl-1-propyl                                           349    166           1-cyclopropyl-1-[1,1-diethyl-2-                                                (hexylamino)ethyl]-3,3-dimethyl-                                               6-ethoxy                                                  350    167           5-iodo-1-isopropyl-1-[3-(methyl-                                               amino)propyl]                                             351    168           1-(3-amino-2-propyl-propyl)-1-                                                 cyclobutyl-3-methyl-8-nitro                               352    169           1-[3-(dimethylamino)-1,2,2-                                                    trimethyl-propyl]-1,4,4-triethyl                          353    170           1-[3-(diethylamino)-2-methyl-                                                  propyl]-1,3-dipropyl-5-methoxy                            354    171           1-[1-propyl-3-(methylamino)-                                                   propyl]-1-propyl-3,3,5-trimethyl                          355    172           1-[4-(dimethylamino)butyl]-1-                                                  methyl                                                    356    173           1-[4-(methylamino)butyl]-1-methyl                         357    174           1-(4-aminobutyl)-1-methyl                                 358    175           1-[4-(hexylamino)butyl]-1-methyl                          359    176           1-cyclobutyl-3,3-dimethyl-1-                                                   [4-(methylamino)-1,1,2-tripropyl-                                              butyl]-4-propyl                                           360    177           4,5-dimethyl-1-ethyl-1-[4-                                                     dimethylamino)-1,1,2,2,3,3-                                                    hexamethylbutyl]                                          361    178           1-(4-amino-2,3,3-trimethyl-butyl)-                                             5-bromo-1-cyclopentyl                                     362    179           1,8-diethyl-1-[3-methyl-4-                                                     (methylamino)butyl]                                       363    180           1-[1,3-diethyl-4-(diethylamino)-                                               butyl]-1-propyl-3,3,5-trimethyl                           364    181           1-[2,3-diethyl-4-(hexylamino)-                                                 butyl]-3,3-dimethyl-1,5-dipropyl                          365    182           1-methyl-1-[3-(1-pyrrolidinyl)-                                                propyl], m.p. 124 - 127° C.                        366    183           1-methyl-1-(3-piperidinopropyl)                           367    184           1-methyl-1-(3-morpholinopropyl)                           368    185           1-methyl-1-(3-piperazinopropyl)                           369    186           1-methyl-1-[3-(4-methyl-1-                                                     piperazinyl)propyl]                                       370    187           1-{3-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]propyl}-1-methyl                              371    188           1-methyl-1-[(1-pyrrolidinyl)-                                                  methyl]                                                   372    189           1-methyl-1-(morpholinomethyl)                             373    190           1-ethyl-3-methyl-1-[(4-methyl-1-                                               piperazinyl)methyl]                                       374    191           1,4-dimethyl-1-(2-piperidinoethyl)                        375    192           1-ethyl-1-(2-morpholinoethyl)                             376    193           1-ethyl-1-{2-[4-(3-hydroxypropyl)-                                             1-piperazinyl]ethyl}                                      377    194           1-propyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                    378    195           1-propyl-1-(2-morpholinoethyl)                            379    196           1-isopropyl-1-(2-piperidinoethyl)                         380    197           3-methyl-1-(2-piperazinoethyl)-                                                1-propyl                                                  381    198           1-ethyl-1-[1-methyl-2-(4-methyl-                                               1-piperazinyl)ethyl]                                      382    199           6-benzyloxy-1-methyl-1-[2-(1-                                                  pyrrolidinyl)ethyl]                                       383    200           5-methyl-1-(2-piperidinoethyl)-                                                1-propyl                                                  384    201           1-cyclopropyl-1-(1,1-diethyl-2-                                                morpholinoethyl)-3,3-dimethyl-6-                                               ethoxy                                                    385    202           8-acetoxy-1-ethyl-3,3,4,4-                                                     tetramethyl-1-(2-methyl-3-                                                     piperazinopropyl)                                         386    203           1-cyclopropyl-4,6-dimethyl-1-                                                  {3-[4-(2-hydroxyethyl)-1-piperazin-                                            yl]-1,1,2,2-tetramethylpropyl}                            387    204           1,3-dimethyl-1-[2,2-dipropyl-3-                                                (1-pyrrolidinyl)propyl]                                   388    205           4,4-dimethyl-1-ethyl-1-(1,1-                                                   dimethyl-3-morpholinopropyl)                              389    206           1-cyclopropyl-1-[1,2-diethyl-3-                                                (4-propyl-1-piperazinyl)propyl]-                                               6-ethoxy                                                  390    207           1-methyl-1-[4-(1-pyrrolidinyl)-                                                butyl]                                                    391    207a          1-{4-[4-(hydroxymethyl)-1-                                                     piperazinyl]butyl}-1-methyl                               392    208           1-[(1,1-diethyl-4-piperidino)butyl]                                            3,3-dimethyl-1-propyl                                     393    209           7-chloro-4,4-diethyl-1-methyl-1-                                               (4-morpholino-1,1,2,2,3-                                                       pentaethylbutyl)                                          394    210           1-butyl-6-fluoro-1-(4-piperazino-                                              1,2,3-trimethylbutyl)-3,3,4-                                                   trimethyl                                                 __________________________________________________________________________

                                      TABLE VIII                                   __________________________________________________________________________            NO. OF THE EXAMPLES                                                            IN WHICH STARTING                                                                            PRODUCT: (PREFIX LISTED BELOW)-                                  MATERIAL IS   1,3,4,9-TETRAHYDROTHIOPYRANO-                             EXAMPLE                                                                               PREPARED      [3,4-b]INDOLE                                             __________________________________________________________________________     395    211           1-methyl-1-[2-(methylamino)ethyl]                         396    212           1-(2-aminoethyl)-1-methyl                                 397    213           1-[(2-hexylamino)ethyl]-1-methyl                          398    214           1-[2-(dimethylamino)ethyl]-1-                                                  methyl, m.p. 119 - 121° C.                         399    215           1-[2-(diethylamino)ethyl]-1-                                                   methyl                                                    400    216           1-methyl-1-[3-(methylamino)propyl]                        401    217           1-(3-aminopropyl)-1-methyl                                402    218           1-[3-(dimethylamino)propyl]-1-                                                 methyl                                                    403    219           1-[3-(hexylamino)propyl]-1-methyl                         404    220           1-[3-(diethylamino)propyl]-1-                                                  methyl                                                    405    221           1-methyl-1-[(methylamino)methyl]                          406    222           1-(aminomethyl)-1-methyl                                  407    223           1-[(dimethylamino)methyl[-1-                                                   methyl                                                    408    224           1-[(hexylamino)methyl]-1-methyl                           409    225           1-[(diethylamino)methyl]-1-                                                    methyl                                                    410    226           1-ethyl-3-methyl-1-[(methylamino)-                                             methyl]                                                   411    228           1-cyclopropyl-1-[(dimethylamino)-                                              methyl)-4-isopropyl                                       412    229           1,4-dimethyl-1-[2-dimethylamino)-                                              ethyl]                                                    413    230           1-ethyl-1-[2-(methylamino)ethyl)                          414    231           1-(2-aminoethyl)-1-ethyl                                  415    232           1-[2-(dimethylamino)ethyl]-1-                                                  ethyl                                                     416    233           1-ethyl-1-[2-(hexylamino)ethyl]                           417    234           1-[2-diethylamino)ethyl]-1-ethyl                          418    235           1-[2-(methylamino)ethyl]-1-propyl                         419    236           1-(aminoethyl)-1-propyl                                   420    237           1-[2-(dimethylamino)ethyl]-1-propyl                       421    238           1-[2-(hexylamino)ethyl]-1-propyl                          422    239           1-[2-(diethylamino)ethyl]-1-propyl                        423    240           1-isopropyl-1-[ 2-(methylamino)-                                               ethyl]                                                    424    241           1-(2-aminoethyl)-1-isopropyl                              425    242           1-[2-(diethylamino)ethyl)-1-                                                   isopropyl                                                 426    243           3-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                  427    245           1-[2-(dimethylamino)ethyl]-3-                                                  methyl-1-propyl                                           428    246           1-[2-(hexylamino)ethyl]-3-methyl-                                              1-propyl                                                  429    247           1-[2-(diethylamino)ethyl]-3-methyl-                                            1-propyl                                                  430    248           1-[1-methyl-2-(methylamino)ethyl]-                                             1-methyl                                                  431    249           1-(2-amino-1-methylethyl)-1-                                                   methyl                                                    432    250           1-[2-(dimethylamino)-1-methyl-                                                 ethyl]-1-methyl                                           433    251           1-[2-(hexylamino)-1-methyl-ethyl]-                                             1-methyl                                                  434    252           1-[2-(diethylamino)-1-methyl-                                                  ethyl]-1-methyl                                           435    253           1-cyclohexyl-1-[1,1-dimethyl-2-                                                (methylamino)ethyl]                                       436    254           8-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                  437    255           1-(2-aminoethyl)-6-bromo-1-propyl                         438    257           1-cyclopropyl-1-[1,1-diethyl-2-                                                (hexylamino)ethyl]-3,3-dimethyl-                                               6-ethoxy                                                  439    258           1-(3-amino-2-propyl-propyl)-1-                                                 cyclobutyl-3-methyl-8-nitro                               440    259           1-[3-(dimethylamino)-1,2,2-                                                    trimethyl-propyl]-1,4,4-triethyl                          441    260           1-[3-(diethylamino)-2-methyl-                                                  propyl]-1,3-dipropyl-5-methoxy                            442    261           1-[1-propyl-3-(methylamino)-                                                   propyl]-1-propyl-3,3,5-trimethyl                          443    263           1-[4-(dimethylamino)butyl]-1-                                                  methyl                                                    444    264           1-[4-(methylamino)butyl]-1-                                                    methyl                                                    445    265           1-[4-(hexylamino)butyl]-1-methyl                          446    266           1-cyclobutyl-3,3-dimethyl-1-                                                   [4-(methylamino)-1,1,2-tripropyl-                                              butyl]-4-propyl                                           447    267           7-chloro-4,4-diethyl-1-[4-                                                     dimethylamino-1,1,2,2,3-                                                       pentaethylbutyl]-1-methyl                                 448    268           1-(4-amino-2,3,3-trimethyl-                                                    butyl)-5-bromo-1-cyclopentyl                              449    269           1,8-diethyl-1-[3-methyl-4-                                                     (methylamino)butyl]                                       450    270           1-[1,3-diethyl-4-(diethylamino)-                                               butyl]-1-propyl-3,3,5-trimethyl                           451    271           1-[2,3-diethyl-4-(hexylamino)-                                                 butyl]-3,3-dimethyl-1,5-dipropyl                          452    272           1-methyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                    453    273           1-methyl-1-(2-piperidinoethyl)                            454    274           1-methyl-1-(2-morpholinoethyl)                            455    275           1-methyl-1-(2-piperazinoethyl)                            456    276           1-methyl-1-[2-(4-methyl-1-                                                     piperazinyl)ethyl]                                        457    277           1-{2-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]ethyl}-1-methyl                               458    278           1-methyl-1-[3-(1-pyrrolidinyl)-                                                propyl]                                                   459    279           1-methyl-1-(3-piperidinopropyl)                           460    280           1-methyl-1-(3-morpholinopropyl)                           461    281           1-methyl-1-(3-piperazinopropyl)                           462    282           1-methyl-1-[3-(4-methyl-1-                                                     piperazinyl)propyl]                                       463    283           1-{3-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]propyl}-1-methyl                              464    284           1-methyl-1-[(1-pyrrolidinyl)-                                                  methyl                                                    465    285           1-methyl-1-(morpholinomethyl)                             466    286           1-ethyl-3-methyl-1-[(4-ethyl-1-                                                piperazinyl)methyl]                                       467    287           1,4-dimethyl-1-(2-piperidino-                                                  ethyl)                                                    468    288           1-ethyl-1-(2-morpholinoethyl)                             469    289           1-ethyl-1-{2-[4-(3-hydroxy-                                                    propyl)-1-piperazinyl]ethyl}                              470    290           1-propyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                    471    291           1-(2-morpholinoethyl)-1-propyl                            472    292           1-isopropyl-1-(2-piperidinoethyl)                         473    293           3-methyl-1-(2-piperazinoethyl)-                                                1-propyl                                                  474    295           1-methyl-1-[1-methyl-2-(4-                                                     methyl-1-piperazinyl)ethyl]                               475    296           6-benzyloxy-1-methyl-1-[2-(1-                                                  pyrrolidinyl)ethyl]                                       476    297           5-methyl-1-(2-piperidinoethyl)-                                                1-propyl                                                  477    298           1-cyclopropyl-1-(1,1-diethyl-                                                  2-morpholinethyl)-3,3-dimethyl-                                                6-ethoxy                                                  478    299           8-acetoxy-1-ethyl-3,3,4,4-                                                     tetramethyl-1-(2-methyl-3-                                                     piperazinopropyl)                                         479    300           1-cyclopropyl-4,6-dimethyl-1-                                                  {3-[4-(2-hydroxyethyl)-1-                                                      piperazinyl]-1,1,2,2-                                                          tetramethylpropyl}                                        480    301           1,3-dimethyl-1-[2,2-dipropyl-                                                  3-(1-pyrrolidinyl)propyl]                                 481    302           4,4-dimethyl-1-ethyl-1-(1,1-                                                   dimethyl-3-morpholinopropyl)                              482    303           1-cyclopropyl-6-ethoxy-1-                                                      [1,2-diethyl-3-(4-propyl-1-                                                    piperazinyl)propyl                                        483    304           1-methyl-1-[4-(1-pyrrolidinyl)-                                                butyl]                                                    484    305           1-{4-[4-(hydroxymethyl)-                                                       piperazinyl]butyl}-1-methyl                               485    306           1-[(1,1-diethyl-4-piperidino)-                                                 butyl]-3,3-dimethyl-1-propyl                              486    307           7-chloro-4,4-diethyl-1-methyl-                                                 1-(4-morpholino-1,1,2,2,3-                                                     pentaethylbutyl)                                          487    308           1-butyl-6-fluoro-1-(4-                                                         piperazino-1,2,3-trimethylbutyl)-                                              3,3,4-trimethyl                                           __________________________________________________________________________

EXAMPLE 488 1,9-DIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, X = O AND Z = CH₂ COOH

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g., 0.04 mole), prepared as described in Example 1, in 150 ml. of tetrahydrofuran is added dropwise to a stirred suspension of sodium hydride (4.4 g. of 55% dispersion) in 200 ml. of tetrahydrofuran. This mixture is heated at 50° C. with stirring for 2 hr. Methyl iodide (14.2 g. 0.1 mole) is added dropwise and heating and stirring is continued for a further 2 hr.

After cooling, water is added until the solution is clear. The tetrahydrofuran is evaporated off under reduced pressure, the residue is partitioned between water and benzene. The aqueous phase is washed once with benzene, made acidic with HCl, and extracted with benzene (3x). The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is crystallized from benzene and then ether-petroleum ether to afford the title compound, m.p. 105° - 108° C., nmr (CDCl₃) δ 1.73 (S, 3H), 2.83 (t, J = 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47 (1H).

The the same manner but replacing methyl iodide with an equivalent amount of ethyl iodide, or propyl iodide, the N-ethyl analog of the title compound, 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 134° - 136° C., and the N-propyl analog of the title compound, 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 120° - 122° C., are obtained, respectively.

By following the procedure of Example 488 but using as starting material an equivalent amount of the acid compounds of formula VII, in which R⁷ is hydrogen, described in Examples 1 to 125, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate organic halide, then the corresponding N-alkylated acid compounds of formula I are obtained. Examples of these latter compounds are listed as products in Tables IX and X together with the appropriate starting material of formula VII and organic halide used for their preparation. In each case the starting material is noted by the Example in which it is prepared.

                                      TABLE IX                                     __________________________________________________________________________            NO. OF THE EXAMPLE        PRODUCT: [(PREFIX LISTED BELOW)-                     IN WHICH STARTING         1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                     MATERIAL IS   ORGANIC     INDOLE-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                               PREPARED      HALIDE      PREFIX//SUFFIX                                __________________________________________________________________________     489    1             CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-methyl//acetic acid,                                                 m.p. 103 - 105° C.                     490    1             CH.sub.2CHBr                                                                               1-methyl-9-vinyl//acetic acid                 491    1             CHCCH.sub.2 Br                                                                             1-methyl-9-propargyl//acetic acid             492    2             n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid             493    2             CH.sub.3 I  1,9-dimethyl//propionic acid                  494    2                                                                                             ##STR53##  1-methyl-9-phenethyl//propionic acid          495    2             1-(3-chloropropyl)-                                                                        1-methyl-9-(3-piperidinopropyl)//                                  piperazine  propionic acid                                496    4             1-(2-chloroethyl)-                                                                         1-methyl-9-[2-(1-pyrrolidinyl)-                                    pyrrolidine ethyl//carboxylic acid                        497    6             CHCCH.sub.2 Br                                                                             1,3-diisopropyl-6-methyl-9-                                                    propargyl//carboxylic acid                    498    7             CH.sub.3 I  6-hydroxy-1,3,3,9-tetramethyl//                                                carboxylic acid                               499    8             CH.sub.3 CHCHBr                                                                            8-ethyl-9-(1-propenyl)-1-propyl//                                              carboxylic acid                               500    10            C.sub.2 H.sub.5 Br                                                                         1-cyclopentyl-4,4,9-triethyl-3,3-                                              dimethyl//carboxylic acid                     501    12            CH.sub.3 I  1-ethyl-9-methyl//acetic acid                 502    12            C.sub. 2 H.sub.5 Cl                                                                        1,9-diethyl//acetic acid                      503    12            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-ethyl//acetic acid                  504    12            2-(dimethylamino)-                                                                         9-[2-(dimethylamino)ethyl//acetic                                  ethyl chloride                                                                             acid                                          505    13            CH.sub.3 I  9-methyl-1-propyl//acetic acid                506    13            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                     507    13            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-propyl//acetic acid                 508    13            CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                             9-methallyl-1-propyl//acetic acid             509    14                                                                                            ##STR54##  9-benzyl-1-isopropyl//acetic acid             510    14            CH.sub.2CHBr                                                                               1-isopropyl-9-vinyl//acetic acid              511    15            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid            512    16            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1,4-diethyl-3-methyl//                                                 acetic acid                                   513    17            CH.sub.3 I  α,1,9-trimethyl//acetic acid            514    18            n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       N                                                                              propyl//acetic acid                           515    19            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-t-butyl//acetic acid                516    20            CH.sub.2CHCH.sub.2 I                                                                       9-allyl-1-butyl//acetic acid                  517    23            CH.sub.3 Cl 1,9-dimethyl-6-methoxy//acetic                                                 acid                                          518    28            CH.sub.2CHBr                                                                               6-nitro-1-propyl-9-vinyl//acetic                                               acid                                          519    32            CHCCH.sub.2 Br                                                                             α,3-dimethyl-1-ethyl-9-propargyl-                                        4,4,5-tripropyl//acetic acid                  520    34            CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-t-butyl-α,α-diisopr                                      opyl-                                                                          3,3,4,4,5-pentaethyl//acetic acid             521    37            C.sub. 2 H.sub.5 I                                                                         7-hydroxy-1-(propyl)-β,β,9-                                          triethyl//propionic acid                      522    38            CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-                                                   nitro-α-propyl//propionic acid          523    41            CH.sub.2C(CH.sub.3)CH.sub.2 Cl                                                             1,4,4-triethyl-9-methallyl-α,.alpha                                      .,β-                                                                      3-tetramethyl//propionic acid                 524    45                                                                                            ##STR55##  1-methyl-6-nitro-α,α,β,.                                      beta.,3-penta- ethyl-9-phenethyl//propion                                      ic acid                                       525    47            1-(3-chloro-                                                                               1-cyclopropyl-α,β-diethyl-7-                            propyl)piperazine                                                                          ethoxy-9-(3-piperidinopropyl)//                                                propionic acid                                526    48            CH.sub.3 I  1,9-dimethyl//butyric acid                    527    48                                                                                            ##STR56##  9-benzyl-1-methyl//butyric acid               528    49            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                          529    51            CH.sub.2CHBr                                                                               1-cyclobutyl-3,3-dimethyl-β,γ,                                      γ,-                                                                      4-tetrapropyl-9-vinyl//butyric                                                 acid                                          530    52            CH.sub.2CHBr                                                                               7-chloro-α,β,β,γ,.g                                      amma.,4-heptaethyl-1-                                                          methyl-9-vinyl//butyric acid                  531    58            C.sub.2 H.sub.5 I                                                                          α-methyl-1,8,9-triethyl//butyric                                         acid                                          532    62            CH.sub.3 I  α,β-diethyl-1,5-dipropyl-3,3,9                                      -                                                                              trimethyl//butyric acid                       __________________________________________________________________________

                                      TABLE X                                      __________________________________________________________________________            NO. OF THE EXAMPLE        PRODUCT: [(PREFIX LISTED BELOW)-                     IN WHICH STARTING         1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                 MATERIAL IS   ORGANIC     INDOLE-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                               PREPARED      HALIDE      PREFIX//SUFFIX                                __________________________________________________________________________     533     3            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-methyl//acetic acid                 534     3            CH.sub.3 I  1,9-dimethyl//acetic acid                     535     3            4-(2-chloroethyl)-                                                                         1-methyl-9-(2-morpholineothyl)                                                 -  morpholine acetic acid                     536    96            n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid             537    96            CH.sub.3 I  1,9-dimethyl//propionic acid                  538    96            CHCCH.sub.2 Br                                                                             1-methyl-9-propargyl//propionic                                                acid                                          539    96            CH.sub.2CHCH.sub.2 Cl                                                                      9-allyl-1-methyl//propionic acid              540    65            CH.sub.3 I  1,9-dimethyl//carboxylic acid                 541    65            1-(3-chloropropyl)-                                                                        1-methyl-9-(3-piperidinopropyl)//                                  piperidine  carboxylic acid                               542    68            CH.sub.3 I  6-hydroxy-1-(1-propyl)-3,3,9-                                                  trimethyl//carboxylic acid                    543    70            CH.sub.3 CHCHBr                                                                            1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                 544    73            CH.sub.3 I  1-ethyl-9-methyl//acetic acid                 545    73            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                      546    73            4-(2-chloroethyl)-                                                                         1-ethyl-9-(2-morpholinoethyl)//                                    morpholine  acetic acid                                   547    73            CHCCH.sub.2 Br                                                                             1-ethyl-9-propargyl//acetic acid              548    74            CH.sub.3 I  9-methyl-1-propyl//acetic acid                549    74            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                     550    74            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-propyl//acetic acid                 551    74            CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                             9-methallyl-1-propyl//acetic acid             552    75            CH.sub.3 I  9-methyl-1-isopropyl//acetic acid             553    75            CH.sub.2CHBr                                                                               1-isopropyl-9-vinyl//acetic acid              554    76            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid             555    76                                                                                           ##STR57##   9-benzyl-3-methyl-1-propyl//acetic                                            acid                                          556    78            CH.sub.3 I  α,1,9-trimethyl//acetic acid            557    79            n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       N                                                                              propyl//acetic acid                           558    84            CH.sub.3 Cl 1,9-dimethyl-6-methoxy//acetic acid           559    89            CH.sub.2CHBr                                                                               α,α-diethyl-1-methyl-9-vinyl-                                      8-                                                                             fluoro//acetic acid                           560    93            C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-1,9-diethyl-1-phenyl-                                       4,4,5-tripropyl//acetic acid                  561    95            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-t-butyl-α,α-diisopr                                      opyl-                                                                          3,3,4,4,5-pentaethyl//acetic acid             562    98            C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-propyl-β,β,9-                                            triethyl//propionic acid                      563    99            CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-nitro-                                             α-propyl//propionic acid                564    106           CH.sub.2CHCl                                                                               1-methyl-6-nitro-α,α,β,.                                      beta.,3-penta-                                                                 ethyl-9-vinyl//propionic acid                 565    108           C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                       1                                                                              triethyl//propionic acid                      566    109           CH.sub.3 I  1,9-dimethyl//butyric acid                    567    109           CH.sub.2CHCH.sub.2 Cl                                                                      9-allyl-1-methyl//butyric acid                568    110           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                          569    112           CH.sub.2CHBr                                                                               1-cyclobutyl-3,3-dimethyl-β,γ,                                      γ,4-                                                                     tetrapropyl-9-vinyl//butyric acid             570    119           C.sub.2 H.sub.5 I                                                                          α-methyl-1,8,9-triethyl//butyric                                         acid                                          __________________________________________________________________________

EXAMPLE 571

By following the procedure of Example 488 but using as the starting material an equivalent amount of the ester compounds of formula I in which R⁷ is hydrogen, obtained prior to hydrolysis in Example 1 and 3 to 125, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of the appropriate organic halide, then the corresponding N-alkylated ester compound of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl or phenyl(lower)alkyl is obtained.

For example, when following the procedure of Example 488, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of its corresponding ethyl ester, described in Example 1, and then use of the same alkyl halide, methyl iodide, affords 1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid ethyl ester.

Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.

By following the procedure of Example 126 but using as starting material an equivalent amount of one of the N-alkylated acid compounds of formula I, described in Examples 488 to 570, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described in Example 126, then the corresponding amide compound of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl phenyl(lower)alkyl and amino(lower)alkyl is obtained. Examples of such amides are listed as products in Tables XI, XII, XIII, and XIV together with the appropriate starting material, noted by the example in which it is prepared, and the amine used for the preparation of the amide.

                                      TABLE XI                                     __________________________________________________________________________            NO. OF THE EXAMPLE       PRODUCT: [(PREFIX LISTED BELOW)-                      IN WHICH STARTING        1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                      MATERIAL IS              INDOLE-1-(SUFFIX LISTED BELOW)]                EXAMPLE                                                                               PREPARED      AMINE      PREFIX//SUFFIX                                 __________________________________________________________________________     572    488 (title compound)                                                                         (CH.sub.3).sub.2 NH                                                                       N,N,1,9-tetramethyl//acetamide                 573    488 (title compound)                                                                         CH.sub.3 NH.sub.2                                                                         N,1,9-tetramethyl//acetamide,                                                  m.p. 136 - 138° C.                      574    488 (title compound)                                                                         NH.sub.3   1,9-dimethyl//acetamide,                                                       m.p. 105 - 106° C.                      575    488 (title compound)                                                                         n-C.sub.6 H.sub.13 NH.sub.2                                                               1,9-dimethyl-N-hexyl//acetamide                576    488 (title compound)                                                                         (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-1,9-dimethyl//acetamide            577    488 (N-ethyl analog)                                                                         (CH.sub.3).sub.2 NH                                                                       9-ethyl-N,N,1-trimethyl//acetamide,            578    488 (N-ethyl analog)                                                                         CH.sub.3 NH.sub.2                                                                         N,1-dimethyl-9-ethyl//acetamide,                                               m.p. 108 - 109° C.                      579    488 (N-ethyl analog)                                                                         NH.sub.3   9-ethyl-1-methyl//acetamide,                                                   m.p. 130 -133° C.                       580    488 (N-propyl analog)                                                                        (CH.sub.3).sub.2 NH                                                                       9-propyl-N,N,1-trimethyl//acetamide                                            m.p. 84 - 87° C.                        581    488 (N-propyl analog)                                                                        CH.sub.3 NH.sub.2                                                                         N,1-dimethyl-9-propyl//acetamide               582    489           CH.sub.3 NH.sub.2                                                                         9-allyl-N,1-dimethylacetamide                  583    491           (CH.sub.3).sub.2 NH                                                                       9-propargyl-N,N,1-trimethyl//                                                  acetamide                                      584    493           (CH.sub.3).sub.2 NH                                                                       N,N,1,9-tetramethyl//propionamide,             585    493           CH.sub.3 NH.sub.2                                                                         N,1,9-trimethyl//propionamide                  586    493           (C.sub.2 H.sub.5).sub.2 NH                                                                1,9-dimethyl-N,N-diethyl//                                                     propionamide                                   587    495           NH.sub.3   1-methyl-9-(3-piperidinopropyl)//                                              propionamide                                   588    495           (CH.sub.3).sub.2 NH                                                                       9-(3-piperidinopropyl-N,N,1-                                                   trimethyl//propionamide                        589    497           CH.sub.3 NH.sub.2                                                                         1,3-diisopropyl-N,6-dimethyl-9-                                                propargyl//carboxamide                         590    498           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N-diethyl-6-hydroxy-1,3,3,9-                                                 tetramethyl//carboxamide                       591    501           CH.sub.3 NH.sub.2                                                                         N,9-dimethyl-1-ethyl//acetamide                592    503           (C.sub.2 H.sub.5).sub.2 NH                                                                9-allyl-N,N,1-triethyl//acetamide              593    504           (CH.sub.3).sub.2 NH                                                                       N,N-dimethyl-9-[2-(dimethylamino)-                                             ethyl]-1-ethyl//acetamide                      594    505           CH.sub.3 NH.sub.2                                                                         N,9-dimethyl-1-propyl//acetamide               595    507           (C.sub.2 H.sub.5).sub.2 NH                                                                9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                      596    514           CH.sub.3 NH.sub.2                                                                         1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                           597    516           n-C.sub.6 H.sub.13 NH.sub.2                                                               9-allyl-1-butyl-N-hexyl//acetamide             598    517           (CH.sub.3).sub.2 NH                                                                       6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                      599    519           CH.sub.3 NH.sub.2                                                                         1-ethyl-9-propargyl-4,4,5-tripropyl-                                           N,α,3-trimethyl//acetamide               600    524           (C.sub.2 H.sub.5).sub.2 NH                                                                N,N,α,α,β,β,3-heptae                                     thyl-1-                                                                        methyl-6-nitro-9-phenethyl//                                                   propionamide                                   601    525           (C.sub.2 H.sub.5).sub.2 NH                                                                1-cyclopropyl-7-ethoxy-N,N,α,β-                                     O                                                                              tetraethyl-9-(3-piperidinopropyl)//propion                                     amide                                          602    526           CH.sub.3 NH.sub.2                                                                         N,1,9-trimethyl//butyramide                    603    527           (CH.sub.3).sub.2 NH                                                                       9-benzyl-N,N,1-trimethyl//                                                     butyramide                                     604    528           NH.sub.2   1,9-diethyl-γ,3-dimethyl//                                               butyramide                                     605    532           CH.sub.3 NH.sub.2                                                                         α,β-diethyl-1,5-dipropyl-N,3,3,                                     9-                                                                             tetramethyl//butyramide                        __________________________________________________________________________

                                      TABLE XII                                    __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT: (PREFIX LISTED BELOW)-                           IN WHICH STARTING    (1,3,4,9-TETREHYDROPYRANO[3,4-b]-                         MATERIAL IS          INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED      AMINE  PREFIX//SUFFIX                                      __________________________________________________________________________     606   488 (title compound)                                                                        pyrrolidine                                                                            1-[(1,9-dimethyl//acetyl]pyrrolidine,               607   488 (title compound)                                                                        piperidine                                                                             1-[(1,9-dimethyl//acetyl]piperidine,                608   488 (title compound)                                                                        morpholine                                                                             1-[(1,9-dimethyl//acetyl]morpholine,                609   488 (title compound)                                                                        N-methyl-                                                                              1-methyl-4-[1,9-dimethyl//acetyl]-                                     piperazine                                                                             piperazine                                          610   488 (N-ethyl analog)                                                                        pyrrolidine                                                                            1-[(9-ethyl-1-methyl//acetyl]-                                                 pyrrolidine                                         611   488 (N-ethyl analog)                                                                        piperidine                                                                             1-[(9-ethyl-1-methyl//acetyl]-                                                 piperidine                                          612    488 (N-propyl analog)                                                                      morpholine                                                                             1-[(1-methyl-9-propyl//acetyl]-                                                morpholine                                          613   488 (title compound)                                                                        N-piperazine-                                                                          1-(2-hydroxyethyl)-4-[1,9-dimethyl//                                   ethanol acetyl]piperazine, γ.sub.max.sup.film                                    1625 cm.sup.-1.                                     614   492          pyrrolidine                                                                            1-[(1-methyl-9-propyl//propionyl]-                                             pyrrolidine                                         615   493          piperidine                                                                             1-[(1,9-dimethyl//propionyl]-                                                  piperidine                                          616   494          morpholine                                                                             1-[(1-methyl-9-phenethyl//propionyl]                                           morpholine                                          617   495          piperazine                                                                             1-[1-methyl-9-(3-piperidinopropyl)//                                           propionyl]piperazine                                618   496          pyrrolidine                                                                            1-{1-methyl-9-[2-(1-pyrrolidinyl)-                                             ethyl]//carbonyl}pyrrolidine                        619   501          morpholine                                                                             1-[(1-ethyl-9-methyl//acetyl]-                                                 morpholine                                          620   502          N-piperazine-                                                                          1-(3-hydroxypropyl)-4-[1,9-diethyl//                                   propanol                                                                               acetyl]piperazine                                   621   505          pyrrolidine                                                                            1-[(9-methyl-1-propyl//acetyl]-                                                pyrrolidine                                         622   507          morpholine                                                                             1-[(9-allyl-1-propyl//acetyl]-                                                 morpholine                                          623   509          piperidine                                                                             1-[(9-benzyl-1-isopropyl//acetyl]-                                             piperidine                                          624   511          piperazine                                                                             1-[(1,9-dipropyl-3-methyl//acetyl]-                                            piperazine                                          625   513          N-ethyl-                                                                               1-ethyl-4-[(α,1,9-trimethyl-α//                            piperazine                                                                             acetyl]piperazine                                   626   525          N-propyl-                                                                              1-propyl-4-[(1-cyclopropyl-α,β-                             piperazine                                                                             diethyl-6-ethoxy-9-(3-piperidino-                                              propyl//propionyl]piperazine                        627   566          pyrrolidine                                                                            1-[(1,9-dimethyl//butyryl]-                                                    pyrrolidine                                         628   527          N-piperazine-                                                                          9-benzyl-1-(hydroxymethyl)-4-                                          methanol                                                                               [(1-methyl//butyryl]piperazine                      629   530          morpholine                                                                             1-[(7-chloro-α,β,β,γ,.gam                                ma.,4,4-                                                                       heptaethyl-1-methyl-9-vinyl//                                                  butyryl]morpholine                                  __________________________________________________________________________

                                      TABLE XIII                                   __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT:[(PREFIX LISTED BELOW)-1,3,-                      IN WHICH STARTING    4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                     EXAMPLE                                                                              PREPARED     AMINE   PREFIX//SUFFIX                                      __________________________________________________________________________     630   534          (CH.sub.3).sub.2 NH                                                                    N,N,1,9-tetramethyl//acetamide                      631   534          CH.sub.3 NH.sub.2                                                                      N,1,9-trimethyl//acetamide                          632   534          NH.sub.3                                                                               1,9-dimethyl//acetamide                             633   534          n-C.sub.6 H.sub.13 NH.sub.2                                                            1,9-dimethyl-N-hexyl//acetamide                     634   534          (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1,9-dimethyl//acetamide                 635   533          (CH.sub.3).sub.2 NH                                                                    9-allyl-N,N,1-trimethyl//acetamide                  636   537          CH.sub.3 NH.sub.2                                                                      N,1,9-trimethyl//propionamide                       637   537          (C.sub.2 H.sub.5).sub.2 NH                                                             1,9-dimethyl-N,N-diethyl//propion-                                             amide                                               638   539          NH.sub.3                                                                               9-allyl-1-methyl//propionamide                      639   539          (CH.sub.3).sub.2 NH                                                                    9-allyl-N,N,1-trimethyl//propionamide               640   541          CH.sub.3 NH.sub.2                                                                      N,1-dimethyl-9-(3-piperidinopropyl)//                                          carboxamide                                         641   542          (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-6-hydroxy-1-propyl-                                                3,3,9-trimethyl//carboxamide                        642   544          CH.sub.3 NH.sub.2                                                                      N,9-dimethyl-1-ethyl//acetamide                     643   546          (C.sub.2 H.sub.5).sub.2 NH                                                             9-(2-morpholinoethyl)-N,N,1-                                                   treiethyl//acetamide                                644   547          (CH.sub.3).sub.2 NH                                                                    N,N-dimethyl-1-ethyl-9-propargyl//                                             acetamide                                           645   548          CH.sub.3 NH.sub.2                                                                      N,9-dimethyl-1-propyl//acetamide                    646   550          (C.sub.2 H.sub.5).sub.2 NH                                                             9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                           647   557          CH.sub.3 NH.sub.2                                                                      1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                                648   558          (CH.sub.3).sub.2 NH                                                                    6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                           649   564          (C.sub.2 H.sub.5).sub.2                                                                N,N,α,α,β,β,3-heptaethyl-                                1-methyl-                                                                      6-nitro-9-vinyl//propionamide                       650   565          (C.sub.2 H.sub.5).sub.2 NH                                                             1-cyclopropyl-6-ethoxy-N,N,α,β,9-                                   pentaethyl//propionamide                            651   566          CH.sub.3 NH.sub.2                                                                      N,1,9-trimethyl//butyramide                         652   567          (CH.sub.3).sub.2 NH                                                                    9-allyl-N,N,1-trimethyl//butyramide                 653   568          NH.sub.2                                                                               1,9-diethyl-γ,3-dimethyl//butyramide          __________________________________________________________________________

                                      TABLE XIV                                    __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW)-1,3,-                     IN WHICH STARTING    4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED     AMINE   PREFIX//SUFFIX                                      __________________________________________________________________________     654   533          pyrrolidine                                                                            1-[(9-allyl-1-methyl//acetyl]-                                                 pyrrolidine                                         655   534          piperidine                                                                             1-[(1,9-dimethyl//acetyl]piperidine                 656   535          morpholine                                                                             1-[(1-methyl-9-(2-morpholino-                                                  ethyl)//acetyl]morpholine                           657   536          pyrrolidine                                                                            1-[(1-methyl-9-propyl//propionyl]-                                             pyrrolidine                                         658   537          piperidine                                                                             1-[(1,9-dimethyl//propionyl]-                                                  piperidine                                          659   538          morpholine                                                                             1-[(1-methyl-9-propargyl//                                                     propionyl]morpholine                                660   539          piperazine                                                                             1-[9-allyl-1-methyl//propionyl]-                                               piperazine                                          661   539          N-methyl-                                                                              1-methyl-4-[9-allyl-1-methyl//                                         piperazine                                                                             propionyl]piperazine                                662   540          pyrrolidine                                                                            1-[1,9-dimethyl//carbonyl]-                                                    pyrrolidine                                         663   541          morpholine                                                                             1-{(1-methyl-9-(3-piperidino-                                                  propyl)//carbonyl}morpholine                        664   544          morpholine                                                                             1[(1-ethyl-9-methyl//acetyl]-                                                  morpholine                                          665   547          N-piperazine-                                                                          1-(3-hydroxypropyl)-4-[(1-ethyl-                                       propanol                                                                               9-propargyl//acetyl]piperazine                      666   548          pyrrolidine                                                                            1-[(9-methyl-1-propyl//acetyl]-                                                pyrrolidine                                         667   549          morpholine                                                                             1-[(1,9-dipropyl//acetyl]-                                                     morpholine                                          668   552          piperidine                                                                             1-[(1-isopropyl-9-methyl//                                                     acetyl]piperidine                                   669   555          piperazine                                                                             1-[9-benzyl-3-methyl-1-propyl//                                                acetyl]piperazine                                   670   556          N-ethyl-                                                                               1-ethyl-4-[α,1,9-trimethyl//                                     piperazine                                                                             acetyl]piperazine                                   671   565          N-propyl-                                                                              1-propyl-4-[(1-cyclopropyl-6-                                          pyrazine                                                                               ethoxy-α,β,9-triethyl//propionyl]-                                  piperazine                                          672   566          pyrrolidine                                                                            1-[(1,9-dimethyl//butyryl]-                                                    pyrrolidine                                         673   567          N-piperazine-                                                                          1-(hydroxymethyl)-4-[9-allyl-1-                                        methanol                                                                               methyl//butyryl]piperazine                          __________________________________________________________________________

EXAMPLE 674

1,9-DIMETHYL-1-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE[I; R¹ = CH₃, R², R³, R⁴, R⁵, AND R⁶ = H, R⁷ = CH₃, X = O AND Y = CH₂ CH₂ N(CH₃)₂ ]

A solution of N,N,1,9-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (12.0 g), described in Example 572, in dry tetrahydrofuran (100 ml.) is added dropwise to a mechanically stirred mixture of lithium aluminium hydride (5 g) in dry tetrahydrofuran (THF) (100 ml.). The mixture is heated at reflux for twenty hours under nitrogen. Water-THF (1:1, 50 ml.) is added to destroy the excess hydride. The mixture is filtered through celite, diluted with water (300 ml.) and extracted three times with ether. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to yield the title compound, nmr (CDCl₃) δ 1.66 (3H), 2.70 (6H), 3.83 (3H).

The corresponding hydrochloric acid addition salt, 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p., 229° - 230° C. after crystallization from methylene dichloride-benzene.

By following the procedure of Example 674 but using as starting material an equivalant amount of one of the N-alkylated amide compounds of formmula VII, described in Examples 573 to 673 instead of N,N1,9-tetramethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetamide then the corresponding N-alkylated amine compound of formula I is obtained. Examples of such compounds are listed as products in Tables XV and XVI together with the appropriate starting material. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE XV                                     __________________________________________________________________________           NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                             PRODUCT: (PREFIX LISTED BELOW)-                           EXAMPLE                                                                              MATERIAL IS PREPARED                                                                          1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE                     __________________________________________________________________________     675   573            1,9-dimethyl-1-[2-(methylamino)ethyl]                     676   574            1-(2-aminoethyl)-1,9-dimethyl                             677   575            1,9-dimethyl-1-[2-(hexylamino)ethyl]                      678   576            1-[2-(diethylamino)ethyl]-1,9-dimethyl,                                        nmr (CDCl.sub.3) δ 0.94 (t, 6H), (S, 3H),                                2.50 (m, 10H).                                            679   577            1-[2-(dimethylamino)ethyl]-9-ethyl-1-                                          methyl, nmr (CDCl.sub.3) δ 1.39 (3H), 1.70                               (3H),                                                                          2.73 (m,12H), corresponding hydrochloric                                       acid addition salt has m.p. 202-205° C.            680   578            9-ethyl-1-methyl-1-[2-(methylamino)ethyl]                 681   579            1-(2-aminoethyl)-9-ethyl-1-methyl                         682   580            1-[2-(dimethylamino)ethyl]-1-methyl-9-                                         propyl, nmr (CDCl.sub.3), δ 1.00 (t, 3H),                                1.65                                                                           (S, 3H), corresponding maleic acid                                             addition salt has m.p. 125-126° C.                 683   581            1-methyl-1-[2-(methylamino)ethyl]-9-propyl                684   582            9-allyl-1-methyl-1-[2-(methylamino)ethyl]                 685   583            1-[2-(dimethylamino)ethyl]-1-methyl-9-                                         propargyl                                                 686   584            1,9-dimethyl-1-[3-(dimethylamino)propyl],                                      nmr (CDCl.sub.3) δ 1.60 (3H), 2.68 (6H),                                 corresponding maleic acid addition salt                                        has m.p. 115-118° C.                               687   585            1,9-dimethyl-1-[3-(methylamino)propyl]                    688   586            1-[3-(diethylamino)propyl]-1,9-dimethyl                   689   587            1-(3-aminopropyl)-1-methyl-9-(3-                                               piperidinopropyl)                                         690   588            1-[3-(dimethylamino)propyl-1-methyl-9-                                         (3-piperidinopropyl)                                      691   589            1,3-diisopropyl-1-methyl-1-(methylamino)-                                      methyl-9-propargyl                                        692   590            1-(diethylamino)methyl-6-hydroxy-1,3,3,9-                                      tetramethyl                                               693   591            1-ethyl-9-methyl-1-[2-(methylamino)ethyl]                 694   592            9-allyl-1-[2-(diethylamino)ethyl]-1-ethyl                 695   593            1,9-bis-[2-(dimethylamino)ethyl]-1-ethyl                  696   594            9-methyl-1-[2-(methylamino)ethyl-1-propyl                 697   595            9-allyl-1-[2-(diethylamino)ethyl]-1-propyl                698   596            1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                        amino)ethyl]-9-propyl                                     699   597            9-allyl-1-butyl-1-[2-(hexylamino)ethyl]                   700   598            1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                       6-methoxy                                                 701   599            1-ethyl-3-methyl-1-[1-methyl-2-(methyl-                                        amino)ethyl]-9-propargyl-4,4,5-tripropyl                  702   600            1-[3-(diethylamino)-1,1,2,2-tetraethyl-                                        propyl]-3-ethyl-1-methyl-6-nitro-9-phenethyl              703   601            1-cyclopropyl-1-[1,2-diethyl-3-(diethyl-                                       amino)propyl]-7-ethoxy-9-(3-piperazinopropyl)             704   602            1,9-dimethyl-1-[4-(methylamino)butyl]                     705   603            9-benzyl-1-[4-(dimethylamino)butyl]-1-                                         methyl                                                    706   604            1,9-diethyl-1-(4-amino-1-methylbutyl)                     707   605            1-[2,3-diethyl-4-(methylamino)butyl]-1,5-                                      dipropyl-3,3,9-trimethyl                                  708   606            1,9-dimethyl-1-[2-(1-pyrrolidinyl)ethyl],                                      nmr (CDCl.sub.3) δ1.62 (s, 3H), 3.74 (s, 3H).       709   607            1,9-dimethyl-1-(2-piperidinoethyl),                                            nmr (CDCl.sub.3) δ1.61 (s, 3H), 2.32 (m, 6H),                            9.81 ((m, 2H), m.p. of corresponding                                           hydrochloric acid addition salt, 233-235° C.       710   608            1,9-dimethyl-1-(2-morpholinoethyl)                        711   609            1,9-dimethyl-1-[2-(4-methyl-1-piperazinyl)-                                    ethyl], nmr (CDCl.sub.3) δ1.56 (s, 3H),                                  2.22 (s, 3), 2.3 (m, 8H).                                 712   610            9-ethyl-1-methyl-1-[2-(1-pyrrolidinyl)-                                        ethyl]                                                    713   611            9-ethyl-1-methyl-1-(2-piperidinoethyl)                    714   612            1-methyl-1-(2-morpholinoethyl)-9-propyl                   715   613            1,9-dimethyl-1-{2-[4-(2-hydroxyethyl)-1-                                       piperazinyl]ethyl}, nmr (CDCl.sub.3) δ1.60                               (s, 3H), 3.70 (s, 3H), m.p. of correspond-                                     ing dihydrochloride salt, m.p. 219-220° C.         716   614            1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                       propyl]                                                   717   615            1,9-dimethyl-1-(3-piperidinopropyl)                       718   616            1-methyl-1-(3-morpholinopropyl)-9-phenethyl               719   617            1,9-bis-(3-piperazinopropyl)-1-methyl                     720   618            1-methyl-1-[(1-piperazinyl)methyl]-9-                                          [2-(1-pyrrolidinyl)ethyl]                                 721   619            1-ethyl-9-methyl-1-(2-morpholinoethyl)                    722   620            1,9-diethyl-1-{2-]4-(3-hydroxypropyl)-1-                                       piperazinyl]ethyl}                                        723   621            9-methyl-1-propyl-1-[2-(1pyrrolidinyl)-                                        ethyl]                                                    724   622            9-allyl-1-(2-morpholinoethyl)-1-propyl                    725   623            9-benzyl-1-isopropyl-1-(2-piperidinoethyl)                726   624            1,9-dipropyl-3-methyl-1-(2-piperazinoethyl)               727   625            1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                        piperazinyl)ethyl]                                        728   626            1-cyclopropyl-1-{1,2-diethyl-3-(4-propyl-                                      1-piperazinyl)propyl}-6-ethoxy-9-(3-                                           piperidinopropyl)                                         729   627            1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                  730   628            9-benzyl-1-{4-[4-(hydroxymethyl)-1-                                            piperazinyl]butyl}-1-methyl                               731   629            7-chloro-4,4-diethyl-1-methyl-1-                                               (4-morpholino-1,1,2,2,3-pentaethylbutyl)-                                      9-vinyl                                                   __________________________________________________________________________

                                      TABLE XVI                                    __________________________________________________________________________            NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                              PRODUCT: (PREFIX LISTED BELOW)-1,3,4,9-                 EXAMPLE                                                                               MATERIAL IS PREPARED                                                                           TETRAHYDROTHIOPYRANO[3,4-b]INDOLE                       __________________________________________________________________________     732    630             1,9-dimethyl-1-[2-(dimethylamino)ethyl],                                       nmr (CDCl.sub.3) δ3.72 (s,6H), 6.40 (s,3H)        733    631             1,9-dimethyl-1-[2-(methylamino)ethyl]                   734    632             1-(2-aminoethyl)-1,9-dimethyl                           735    633             1,9-dimethyl-1-[2-(hexylamino)ethyl]                    736    634             1-[2-(diethylamino)ethyl]-1,9-dimethyl                  737    635             9-allyl-1-[2-(dimethylamino)ethyl]-1-methyl             738    636             1,9-dimethyl-1-[3-(methylamino)propyl]                  739    637             1-[3-(diethylamino)propyl]-1,9-dimethyl                 740    638             9-allyl-1-(3-aminopropyl)-1-methyl                      741    639             9-allyl-1-[3-(dimethylamino)propyl]-1-                                         methyl                                                  742    640             1-methyl-1-[(methylamino)methyl]-9-                                            (3-piperidinopropyl) -743 641 1-[(diethylamino)meth                            yl]-6-hydroxy-1-propyl-                                                        3,3,9-trimethyl                                         744    642             1-ethyl-9-methyl-1-[2-(methylamino)ethyl]               745    643             1-[2-(diethylamino)ethyl]-1-ethyl-9-                                           (2-morpholinoethyl) -746 644 1-[2-(dimethylamino)et                            hyl]-1-ethyl-9-propargyl                                747    645             9-methyl-1-[2-(methylamino)ethyl]-1-propyl              748    646             9-allyl-1-[2-(diethylamino)ethyl]-1-propyl              749    647             1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                        amino)ethyl]-9-propyl                                   750    648             1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                       6-methoxy                                               751    649             1-[3-(diethylamino)-1,1,2,2-tetramethyl-                                       propyl)-3-ethyl-6-nitro-9-vinyl                         752    650             1-cyclopropyl-1-[1,2-diethyl-3-                                                (diethylamino)propyl]-6-ethoxy-9-ethyl                  753    651             1,9-dimethyl-1-[4-(methylamino)butyl]                   754    652             9-allyl-1-[4-(dimethylamino)butyl]-1-                                          methyl                                                  755    653             1-[4-amino-1-methylbutyl)-1,9-diethyl-3-                                       methyl                                                  756    654             9-allyl-1-methyl-1-[ 2-(1-pyrrolidinyl)-                                       ethyl]                                                  757    655             1,9-dimethyl-1-(2-piperidinoethyl)                      758    656             1-methyl-1,9-bis(2-morpholinoethyl)                     759    657             1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                       propyl]                                                 760    658             1,9-dimethyl-1-(3-piperidinopropyl)                     761    659             1-methyl-1-(3-morpholinopropyl)-9-                                             propargyl                                               762    660             9-allyl-1-methyl-1-(3-piperazinopropyl)                 763    661             9-allyl-1-methyl-1-[3-(4-methyl-1-                                             piperazinyl)propyl]                                     764    662             1,9-dimethyl-1-[1-pyrrolidinyl)methyl]                  765    663             1-methyl-1-(morpholinomethyl)-9-                                               (3-piperidinopropyl)                                    766    664             1-ethyl-9-methyl-1-(2-morpholinoethyl)                  767    665             1-ethyl-1-{2-[4-(3-hydroxypropyl)-1-                                           piperazinyl]ethyl}-9-propargyl                          768    666             9-methyl-1-propyl-1-[2-(1-pyrrolidinyl)-                                       ethyl]                                                  769    667             1,9-dipropyl-1-(2-morpholinoethyl)                      770    668             1-isopropyl-9-methyl-1-(2-piperidinoethyl)              771    669             9-benzyl-3-methyl-1-(2-piperazinoethyl)-                                       1-propyl                                                772    670             1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                        piperazinyl)ethyl]                                      773    671             1-cyclopropyl-6-ethoxy-9-ethyl-1-[1,2-                                         diethyl-3-(4-propyl-1-piperazinyl)propyl                774    672             1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                775    673             9-allyl-1-{4-[4-(hydroxymethyl)-1-                                             piperazinyl]butyl}1-methyl                              __________________________________________________________________________

EXAMPLE 776 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXAMIDE (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, and Z = CONH₂

By following the procedure of Example 1 but using boron trifluoride-ethanole as the acid catalyst and an equivalent amount of pyruvamide instead of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p. 188° - 189° C. after recrystallization from benzene-hexene, identical with the product of Example 133, is obtained.

In the same manner but using an equivalent amount of the appropriate starting material of formula II together with the appropriate α-, β-, γ- or δ-ketoamide, the products listed in Tables III and IV are obtained. For example, by using tryptophol (II; R², R³ R⁴, R⁵, R⁶ = H and X¹ = OH) and the β-ketoamide, N,N-dimethyl-acetoacetamide, in the procedure of this Example, N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, identical with the product of Example 126, is obtained.

EXAMPLE 777 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXALDEHYDE

A mixture of the starting material, tryptophol (32.2 g., 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is refluxed for 11/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol acetate is obtained as an oil, nmr(CDCl₃) δ 1.52 (S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at room temperature. To this solution is added dropwise 20 ml of 10NaOH. Hydrolysis is immediate. Most of the methanol is removed under reduced pressure, and water is added. The mixture is rendered neutral and extracted with chloroform. The chloroform extract is dried and evaporated to afford the primary alcohol, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol, m.p. 145° - 147° C., nmr(CDCl₃), δ 1.43 (s,3H), 2.68 (t, J = 5.5 cps, 2H), 3.65 (d, J = 6 cps, 2H), 3.86 (t, J = 5.5 cps, 2H), after crystallization from benzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled, stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63 ml of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid (1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reaction is stirred at room temperature under nitrogen for 5hr. The reaction mixture is now diluted with 600 ml of ether, followed by the dropwise addition of a solution of oxalic acid (7.56 g) in 21 ml of methanol. After thirty minutes, water (600 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO₄) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as eluate, nmr (CDCl₃) δ1.59 (s,3H), 2.84 (t, J = 5.5 cps, 2H), 4.15 (t, J = 5.5 cps, 2H).

EXAMPLE 778

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde, described in Example 777, is treated with an excess of dimethylamine according to the method of K. N. Campbell, et al., J. Amer. Chem. Soc., 70, 3868 (1948), to yield the corresponding Schiff base. Reduction of the latter compound with sodium borohydride according to the procedure described by E. Schenker, Angew Chem., 73, 81 (1961), affords 1-[2-(dimethylamino)]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, identical to the product of Example 309.

By following the procedures of Examples 777 and 778 in sequence, but using a starting material in Example 777 an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VI, described above, and in the procedure of Example 778 using an appropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance, then the respective compounds of formula I, for example, those described in Example 309 (other than the title compond) to 487, inclusive, are obtained.

More specifically exemplified, the use of indole-3-ethanethiol, acetonyl acetate and n-hexylamine in the manner just described for the starting material of formula II, the appropriate ketoalcohol lower alkyl ester and amine, respectively, yields 1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole

EXAMPLE 779

Oxidation of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde, described in Example 777, with silver oxide according to the method of Delepine and Bonnet, cited above, affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr (CDCl₃) δ1.79 (s, 3H), 2.83 (t, 2H), 4.17 (t, 2H), 9.20 (1H), identical to the product obtained in Example 4.

By following the procedures of Examples 777 and 779, in sequence, but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VI, in which R¹ is as defined in the first instance and Z is CH₂ OCOR²⁰ or Alk¹ CH₂ OCOR²⁰ wherein R²⁰ and Alk¹ are as defined in the first instance, then the acid compound of formula I in which R⁷ is hydrogen and Y is COOH or Alk¹ COOH wherein Alk¹ is as defined above, for example, the respective products of Examples 1 to 125, inclusive, are obtained.

More specifically exemplified, according to the procedures of Examples 777 and 779, the use of tryptophol and 6-acetoxy-2-hexanone, affords 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-butyric acid, identical to the product of Example 48. Similarly, the use of tryptophol and 5-acetoxypentan-2-one affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, identical to the product of Example 2.

EXAMPLE 780 1-(AMINOMETHYL)-1METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE(I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ NH₂

A solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde (547 mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5 ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml) is heated at 50° - 60° C. for 5 min. and then kept at 4° C. for 16 hr. The precipitate is collected and recrystallized from ethanol water to afford 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde oxime, m.p. 176° - 178° C.

The latter compound (230 mg) in dry THF (10 ml) is added dropwise to a stirred mixture of lithium aluminum hydride (200 mg) in 15 ml. of THF at ice bath temperature. The mixture is stirred for 1 hr., during which time it is allowed to come to room temperature. Excess lithium aluminum hydride is destroyed by the careful addition of H₂ O/THF(1:1). Insoluble material is collected on a filter and the filtrate is concentrated. The concentrate is taken up in ether. The ether solution is dried (MgSO₄), filtered and concentrated to afford the title compound, identical with the compound of the same name described in Example 316.

EXAMPLE 781 1-METHYL-1-[3-(1-PYRROLIDINYL)PROPYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE]I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ AND R⁷ = H, X = O AND Y = ##STR58##

To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentratio of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl₃) δ1.33 (3H); 1.93 (4H), 2.75 (2H).

A solution of the latter compound (250 mg., 0.9 millimoles) in 10 ml of THF and 1.5 ml of pyrrolidine is heated at reflux for 16 hr. The mixture is concentrated under reduced pressure and the residue partitioned between 5% sodium carbonate and chloroform. The organic phase is washed with water, dried (Na₂ SO₄), filtered and evaporated under reduced pressure to give the title compound, identical with the product of Example 365.

By following the procedure of Example 781 but using as starting material an equialent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate β-, γ-, or δ-haloketone of formula VI, described above, and the appropriate amine of formula HNR⁸ R⁹, described above, then the respective compounds of formula I, for example those described in Examples 309 to 487, inclusive, are obtained.

EXAMPLE 782 1-[(ETHYLAMINO)METHYL]-1-METHYL-1,3,4,9-TETRAHYDROPYRANOL[3,4b]INDOLE(I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O and Y = CH₂ NHCH₃)

A mixture of tryptophol (3.86 g; II, R², R³, R⁴, R⁵, R⁶ = H and X¹ =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. R_(f) values of the amide and tryptophol are equal.

The latter product (2.4 g) is dissolved in 80 ml of dry THF and added to a suspension of lithium aluminum hydride in 200 ml of THF.

The resultant slurry is stirred and heated to reflux for 2 hr. cooled and 2.4 g of lithium aluminum hydride is added. The mixture is then refluxed with stirring overnight. The reaction mixture is decomposed with 22.4 ml of water added dropwise over 3 hr. upon stirring and cooling. Stirring is continued for 1 hr. the precipitate is separated by filtration and the filtrate is dried (MgSO₄). Removed of the solvent by evaporation yield the title compound, nmr (DMSO-d₆) δ1.18 (t, 3H), 1.62 (s, 3H), 2.80 (t, 2H), identical to the product of Example 319.

The corresponding hydrochloric acid addition salt, 1-[(ethylamino)methyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p. 242° - 243° C., after recrystallization from isopropanol-ether.

By following the procedure of Example 782 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, and using an equivalent amount of an appropriate ketoamide of formula ##STR59## described above, then the respective secondary amine compounds of formula I are obtained.

EXAMPLE 783 1-METHYL-1-NITROMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O and Z = CH₂ NO₂

To a solution of 322 mg of tryptophol (II, R², R³, R⁴, R⁵, R⁶ = H and X¹ =OH) and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml of benzene is added five drops of boron trifluoride etherate and three drops of trifluoroacetic acid. The reaction mixture is stirred and heated at reflux under water-separator for 18 hr. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water, saturated brine solution, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Elution with chloroform gives the title compound, δ_(max) ^(CHCl).sbsp.3 3450, 1550cm³¹ 1, nmr (CDCl₃) δ1.68 (s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).

Reduction of the latter compound with lithium aluminum hydride according to the procedure of Example 309 affords 1-(aminomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, identical with the product of Example 316.

By following the procedure of Example 783 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, and using an equivalent amount of an appropriate nitroketone of formula ##STR60## described above, then the respective primary amine compounds of formula I are obtained.

EXAMPLE 784 6-HYDROXY-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII; R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁷ = H, R⁶ = 6-OH, X = O, AND Z = CH₂ COOH)

A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 25, in 250 ml. of anhydrous ethanol, and 1.1 g of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound, m.p. 170° - 171° C.

The corresponding benzylamine salt is prepared by the mixing of equimolar ethereal solutions of benzylamine and the above product. The resulting solid is recrystallized from acetonitrile to afford 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid benzylamine salt, m.p. 191° - 193° C. The corresponding acetate is prepared by allowing a mixture of the title compound and a five molar excess of acetic anhydride in pyridine solution to stand for 24 hr. Dilution of the mixture with water extraction with ether and recrystallization of the extract residue from benzene-petroleum ether, affords 6-acetoxy-1-methyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid, identical with the product of Example 24.

EXAMPLE 785 1,1-DIMETHYL-1,3,4,9-TETRAHYDROPYRANO-[3,4-b]INDOLE (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶, AND R⁷ = H AND Z = CH₃)

A solution of tryptophol (8 g, 0.05M), acetone (5 g) and p-toluenesulfonic acid (100 mg) in 100 ml of benzene containing hydrated alkali-aluminium silicate (Molecular Sieves No. 4) is heated to reflux for 1 hr. More p-toluenesulfonic acid (100 mg) and the ketone, acetone (3 g), is added and the reflux continued for a further 1.5 hr.

The mixture is filtered and the filtrate is washed with 5% sodium bicarbonate and water. After drying over sodium sulfate the benzene is evaporated under reduced pressure affording a solid. Chromatography of this solid on silica gel using 30% ethyl acetate in benzene as eluant gives a white product which is recrystallized once from benzene-petroleum ether to give the title compound, m.p. 142° - 144° C., nmr (CDCl₃) δ2.76 (t, J = 5.5 cps, 2H), 4.03 (t, J = 5.5 cps, 2H).

The procedure of Example 785 is followed to prepare other compounds of formula VII in which R¹, R², R³, R⁴ R⁵, R⁶ are as defined in the first instance, R⁷ is hydrogen and Z is lower alkyl or phenyl(lower)alkyl. Examples of such compounds are listed in Tables XVII and XVIII. In each example an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in Example 785, together with the appropriate ketone.

                                      TABLE XVII                                   __________________________________________________________________________      STARTING MATERIAL OF FORMULA II                                                                                ##STR61##    PRODUCT: (PREFIX LISTED                                                        BELOW)-1,3,4,9- TETRAHYDROPY                                                   RANO-                            EX.                                                                               R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                               X     R.sup.1                                                                              Z       [3,4-b]-INDOLE                   __________________________________________________________________________     786                                                                               H   H   H   H   H      O     C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                       1-ethyl-1-propyl                787                                                                               H   H   H   H   H      O     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1-methyl-1-propyl               788                                                                               H   H   H   H   H      O     C.sub.2 H.sub.5                                                                       ##STR62##                                                                              1-ethyl-1-phenethyl             789                                                                               H   H   H   H   H      O     CH.sub.3                                                                              ##STR63##                                                                              1-benzyl-1-methyl, m.p.                                                        141-145° C               790                                                                               CH.sub.3                                                                           H   H   H   H      O     CH.sub.3                                                                             CH.sub.3 1,1,3-trimethyl                 791                                                                               n-C.sub.3 H.sub.7                                                                  H   H   H   H      O     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,3-dipropyl-1-methyl           792                                                                               CH.sub.3                                                                           CH.sub.3                                                                           H   H   H      O                                                                                     ##STR64##                                                                           CH.sub.3 1-cyclopropyl-1,3,3-                                                           trimethyl                       793                                                                               C.sub.2 H.sub.5                                                                    H   C.sub.2 H.sub.5                                                                    H   H      O                                                                                     ##STR65##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclohexyl-3,4-diethyl-                                                      1-propyl                        794                                                                               H   H   CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H      O     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                       1,4-dimethyl-1,4-dipropyl       795                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H      O     CH.sub.3                                                                              ##STR66##                                                                              1-benzyl-1,3,3,4,4-penta-                                                      methyl                          796                                                                               H   H   H   H   4-CH.sub.3                                                                            O                                                                                     ##STR67##                                                                           CH.sub.3 1-cyclopropyl-1,5-dimethyl                                                     O                               797                                                                               H   H   H   H   5-C.sub.2 H.sub.5                                                                     O                                                                                     ##STR68##     1-cyclopentyl-6-ethyl           798                                                                               C.sub.2 H.sub.5                                                                    H   H   H   6-OCH.sub.3                                                                           O     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         7-methoxy-1,1,3-triethyl        799                                                                               CH.sub.3                                                                           CH.sub.3                                                                           H   H   7-OC.sub.2 H.sub.5                                                                    O     CH.sub.3                                                                             CH.sub.3 8-ethoxy-1,1,3,3-tetra-                                                        methyl                          800                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-NO.sub.2                                                                            O     C.sub.2 H.sub.5                                                                       ##STR69##                                                                              1,3-diethyl-6-nitro-                                                           1-(3-phenylpropyl)              801                                                                               H   H   H   H   7-NO.sub.2                                                                            O     CH.sub.3                                                                             CH.sub.3 1,1-dimethyl-8-nitro            802                                                                               H   H   H   CH.sub. 3                                                                          6-CH.sub.3 COO                                                                        O     C.sub.2 H.sub.5                                                                      CH.sub.3 7-acetoxy-1,4-dimethyl-                                                        1-ethyl                         803                                                                               n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  H   H   5-C.sub.2 H.sub.5 COO                                                                 O                                                                                     ##STR70##                                                                            ##STR71##                                                                              1-benzyl-1-cyclopropyl-                                                        3,3-dipropyl-6-propionyl-                                                      oxy                             804                                                                               H   H   H   H   4-Cl   O                                                                                     ##STR72##                                                                           CH.sub.3 5-chloro-1-cyclopropyl-                                                        methyl                          805                                                                               CH.sub.3                                                                           H   H   H   6-Cl   O                                                                                     ##STR73##                                                                            ##STR74##                                                                              1-benzyl-7-chloro-                                                             1-cyclohexyl-3-methyl           806                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-Br   O     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         6-bromo-1,1,3-triethyl          807                                                                               H   H   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  7-Br   O     n-C.sub.3 H.sub.7                                                                    CH.sub.3 8-bromo-1-methyl-1,4,4-                                                        tripropyl                       808                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-F    O     CH.sub.3                                                                             CH.sub.3 5-fluoro-1,1,3,3,4,4-                                                          hexamethyl                      809                                                                               H   H   H   H   6-F    O                                                                                     ##STR75##                                                                           n-C.sub.3 H.sub.7                                                                       1-cyclopropyl-7-fluoro-                                                        1-propyl                        810                                                                               CH.sub.3                                                                           H   CH.sub. 3                                                                          H   7-I    O     CH.sub.3                                                                              ##STR76##                                                                              8-iodo-1-phenethyl-                                                            1,3,4-trimethyl                 811                                                                               H   H   H   H   5-I    O     CH.sub.3                                                                             CH.sub.3 1,1-dimethyl-6-iodo             __________________________________________________________________________

                                      TABLE XVIII                                  __________________________________________________________________________      STARTING MATERIAL OF FORMULA II                                                                                ##STR77##    PRODUCT: (PREFIX LISTED                                                        BELOW)-1,3,4,9- TETRAHYDROTH                                                   IOPYRANO-                        EX.                                                                               R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                               X     R.sup.1                                                                              Z       [3,4-b]INDOLE                    __________________________________________________________________________     812                                                                               H   H   H   H   H      S     CH.sub.3                                                                             CH.sub.3                                                                               1,1-dimethyl                     813                                                                               H   H   H   H   H      S     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                      1-methyl-1-propyl                814                                                                               H   H   H   H   H      S     C.sub.2 H.sub.5                                                                       ##STR78##                                                                             1-ethyl-1-phenethyl              815                                                                               H   H   H   H   H      S     CH.sub.3                                                                              ##STR79##                                                                             1-benzyl-1-methyl                816                                                                               CH.sub.3                                                                           H   H   H   H      S     CH.sub.3                                                                             CH.sub.3                                                                               1,1,3-trimethyl                  817                                                                               n-C.sub.3 H.sub.7                                                                  H   H   H   H      S     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                      1,3-dipropyl-1-methyl            818                                                                               CH.sub.3                                                                           H   H   H   H      S                                                                                     ##STR80##                                                                           CH.sub.3                                                                               1-cyclopropyl-1,3,3,-                                                          trimethyl                        819                                                                               C.sub.2 H.sub.5                                                                    H   C.sub.2 H.sub.5                                                                    H   H      S                                                                                     ##STR81##                                                                           n-C.sub.3 H.sub.7                                                                      1-cyclohexyl-3,4-diethyl                                                       1-propyl                         820                                                                               H   H   CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H      S     CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                      1,4-dimethyl-1,4-dipropyl        821                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H      S     CH.sub.3                                                                              ##STR82##                                                                             1-benzyl-methyl-1,3,3,4,                                                       4-pentamethyl                    822                                                                               H   H   H   H   4-CH.sub.3                                                                            S                                                                                     ##STR83##                                                                           CH.sub.3                                                                               1-cyclopropyl-1,5- dimethyl                                                    O                                823                                                                               H   H   H   H   5-C.sub.2 H.sub.5                                                                     S                                                                                     ##STR84##    1-cyclopentyl-6-ethyl            824                                                                               C.sub.2 H.sub.5                                                                    H   H   H   6-OCH.sub.3                                                                           S     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        7-methoxy-1,1,3-triethyl         825                                                                               CH.sub.3                                                                           CH.sub.3                                                                           H   H   7-OC.sub.2 H.sub.5                                                                    S     CH.sub.3                                                                             CH.sub.3                                                                               8-ethoxy-1,1,3,3-                                                              tetramethyl                      826                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-NO.sub.2                                                                            S     C.sub.2 H.sub.5                                                                       ##STR85##                                                                             1,3-diethyl-6-nitro-                                                           1-(3-phenylpropyl)               827                                                                               H   H   H   H   7-NO.sub.2                                                                            S     CH.sub.3                                                                             CH.sub.3                                                                               1,1-dimethyl-8-nitro             828                                                                               H   H   H   CH.sub.3                                                                           6-CH.sub.3 COO                                                                        S     C.sub.2 H.sub.5                                                                      CH.sub.3                                                                               7-acetoxy-1,4-dimethyl-                                                        1-ethyl                          829                                                                               n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  H   H   5-C.sub.2 H.sub.5 COO                                                                 S                                                                                     ##STR86##                                                                            ##STR87##                                                                             1-benzyl-1-cyclopropyl-                                                        3,3-dipropyl-6- propionyloxy                                                   `                                830                                                                               H   H   H   H   4-Cl   S                                                                                     ##STR88##                                                                           CH.sub.3                                                                               5-chloro-1-cyclopropyl-1-                                                      methyl                           831                                                                               CH.sub.3                                                                           H   H   H   6-Cl   S                                                                                     ##STR89##                                                                            ##STR90##                                                                             1-benzyl-7-chloro-1-                                                           cyclohexyl-3-methyl              832                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-Br   S     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        6-bromo-1,1,3-triethyl           833                                                                               H   H   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  7-Br   S     n-C.sub.3 H.sub.7                                                                    CH.sub.3                                                                               8-bromo-1-methyl-1,4,4-                                                        tripropyl                        834                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-F    S     CH.sub.3                                                                             CH.sub.3                                                                               5-fluoro-1,1,3,3,4,4-                                                          hexamethyl                       835                                                                               H   H   H   H   6-F    S                                                                                     ##STR91##                                                                           n-C.sub.3 H.sub.7                                                                      1-cyclopropyl-7-fluoro-                                                        1-propyl                         836                                                                               CH.sub.3                                                                           H   CH.sub.3                                                                           H   7-I    S     CH.sub.3                                                                              ##STR92##                                                                             8-iodo-1-phenethyl-                                                            1,3,4-trimethyl                  837                                                                               H   H   H   H   5-I    S     CH.sub.3                                                                             CH.sub.3                                                                               1,1-dimethyl-6-iodo              __________________________________________________________________________

EXAMPLE 838 1,1-DIMETHYL-9-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE (I; R¹ AND Y = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, AND R⁷ = CH₂ CH₂ N(CH₃)₂ ]

To 4.2 g. of a 50% dispersion of sodium hydride in 20 ml. of dimethylformamide is added a solution of 7 g. of 1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, described in Example 785, in 20 ml. of dimethylformamide. The addition is made dropwise at room temperature while stirring vigorously. The mixture is heated for 1 hr. at 40° C. Then an excess of the organic halide, dimethylaminoethyl chloride (free base obtained from 15 g. of the hydrochloride) is added and stirring continued at 40° C overnight.

The reaction mixture is poured into ice-water, acidified with 6NHCl and washed with ether. The aqueous phase is rendered alkaline with 10% NaOH and extracted with benzene. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield the title compound, nmr (CDCl₃) δ1.63 (6H), 2.36 (6H), 2.79 (m, 4H), 4.10 (m, 4H), 7.18 (m, 4H).

The corresponding hydrochloric acid addition salt, 1,1-dimethyl-9-[(2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p. 198° - 200° C., after crystallization from methanol-ether.

The procedure of Example 838 is followed to prepare other compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is aminoalkyl as defined above and Y is lower alkyl or phenyl(lower)alkyl. Examples of such compounds are listed in Tables XIX and XX. In each example an equivalent amount of the appropriate starting material of formula VII in which R¹, R², R³, R⁴ R⁵, R⁶ are as defined in the first instance, R⁷ is hydrogen and Z is lower alkyl or phenyl(lower)alkyl, described in Examples 785 to 837, is used in place of 1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole if required. In each case the starting material of formula VII is noted by the example in which it is prepared.

                                      TABLE XIX                                    __________________________________________________________________________           NO. OF THE                                                                     EXAMPLE IN                                                                     WHICH                                                                          STARTING                PRODUCT: (PREFIX LISTED BELOW)-                        MATERIAL IS                                                                             ORGANIC        1,3,4,9-TETRAHYDROPYRANO-                        EXAMPLE                                                                              PREPARED HALIDE         [3,4-b]INDOLE                                    __________________________________________________________________________     839   785      (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                         1,1-dimethyl-9-[3-(dimethyl-                                                   amino)propyl], nmr (CDCl.sub.3)                                                δ1.62 (6H), 2.00 (m, 2H), 2.25                                           (6H), corresponding hydrochloric                                               acid addition salt has m.p.                                                    201 - 203° C.                             840   785      CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1,1-dimethyl-9-[2-(methylamino)-                                               ethyl]-841 785 i-C.sub.3 H.sub.7 NH(CH.sub.2                                   ).sub.2 Cl 1,1-dimethyl-9-[2-(isopropyl-                                       amino)ethyl]                                     842   786      NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                               9-(3-amino-2,2-dimethylethyl)-                                                 1-ethyl-1-propyl                                 843   787      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         9-[2-(dimethylamino)ethyl]-1-                                                  methyl-1-propyl                                  844   788      C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         1-ethyl-9-[3-(ethylamino)propyl]-                                              1-phenethyl                                      845   789      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-9-[2-(dimethylamino)-                                                 ethyl]-1-methyl, nmr(CDCl.sub.3 )                                              δ1.55 (s, 3H), 2.92 (6H), 3.95                                           (2H), corresponding hydrochloric                                               acid addition salt has m.p.                                                    218 - 220° C.                             846   789      CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1-benzyl-1-methyl-9-[2-(methyl-                                                amino)ethyl]                                     847   789      NH.sub.2 (CH.sub.2).sub.3 Cl                                                                  9-(4-aminobutyl)-1-benzyl-1-                                                   methyl                                           848   790      (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2 Cl                                            9-[1,2-dimethyl-3-(dimethyl-                                                   amino)propyl]-1,1,3-trimethyl                    849   791      (C.sub.2 H.sub.5).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                                          9-[2-(dimethylamino)-2-                                                        ethylethyl]-1,3-dipropyl-1-                                                    methyl                                           850   792      CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                1-cyclopropyl-9-[3-(methyl-                                                    amino)propyl]-1,3,3-trimethyl                    851   793      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-cyclohexyl-3,4-diethyl-                                                      9-[2-(dimethylamino)ethyl]-                                                    1-propyl                                         852   794      (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                                1,4-dimethyl-1,4-dipropyl-9-                                                   [3-(dipropylamino)propyl]                        853   795      (CH.sub.3).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2 Cl                                            1-benzyl-9-[2-(dimethylamino)-                                                 2-propylethyl]-1,3,3,4,4-                                                      pentamethyl                                      854   796      (CH.sub.3).sub.2 N[ CH(n-C.sub.3 H.sub.7)].sub.3 CH.sub.2                      Cl             1-cyclopropyl-1,5-dimethyl-9-                                                  [4-(dimethylamino)-2,3,4-                                                      tripropylbutyl]                                  855   797      (C.sub.2 H.sub.5).sub.2 N(CH.sub.2).sub.2 Cl                                                  1-cyclopentyl-9-[2-(diethyl-                                                   amino)ethyl]-6-ethyl                             856   798      CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                7-methoxy-9-[3-(methylamino)-                                                  propyl]-1,1,3-triethyl                           857   799      n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       8-ethoxy-9-[2-(propylamino)-                                                   ethyl]-1,1,3,3-tetramethyl                       858   800      i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       1,3-diethyl-9-[2-(isopropyl-                                                   amino)ethyl]-6-nitro-1-                                                        (3-phenylpropyl)                                 859   801      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1,1-dimethyl-9-[2-(dimethyl-                                                   amino)ethyl]-8-nitro                             860   802      C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         7-acetoxy-1,4-dimethyl-1-ethyl-                                                9-[3-(ethylamino)propyl]                         861   803      (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-1-cyclopropyl-9-[2-                                                   (dimethylamino)ethyl-3,3-                                                      dipropyl-6-propionyloxy                          862   804      n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                       5-chloro-1-cyclopropyl-1-                                                      methyl-9-[3-(propylamino)-                                                     propyl                                           863   805      1-(3-chloropropyl)-                                                                           1-benzyl-7-chloro-1-cyclohexyl-                                 pyrrolidine    3-methyl-9-[3-(lpyrrolidinyl)-                                                 propyl]                                          864   806      1-(2-chloroethyl)-                                                                            6-bromo-9-(2-piperidinoethyl)-                                  piperidine     1,1,3-triethyl                                   865   807      4-(2-chloroethyl)-                                                                            8-bromo-1-methyl-9-(2-morpholino-                               morpoline      ethyl)-1,4,4-tripropyl                           866   808      1-(3-chloropropyl)-                                                                           5-fluoro-1,1,3,3,4,4-hexamethyl-                                piperazine     9-(piperazinopropyl)                             867   809      1-(3-chloroethyl)-4-                                                                          1-cyclopropyl-7-fluoro-9-                                       methylpiperazine                                                                              [2-(4-methyl-1-piperazinyl)-                                                   ethyl]-1-propyl                                  868   810      1-(2-chloroethyl)-4-                                                                          9-{2-[4-(hydroxyethyl)-1-                                       (hydroethyl)piperazine                                                                        piperazinyl]ethyl-8-iodo-1-                                                    phenethyl-1,3,4-trimethyl                        869   811      1-(2-chloroethyl)-                                                                            1,1-dimethyl-6-iodo-9-[2-(1-                                    pyrrolidine    pyrrolidinyl)ethyl]                              870   785      1-(3-chloropropyl)-                                                                           1,1-dimethyl-9-(3-piperidino-                                   piperidine     propyl)                                          871   785      4-(4-chlorobutyl)-                                                                            1,1-dimethyl-9-(4-morpholino-                                   morpholine     butyl)                                           872   789      1-(4-chlorobutyl)-                                                                            9-[4-(4-methyl-1-piperazinyl)-                                  4-methylpiperazine                                                                            butyl]                                           873   789      1-(2-chloroethyl)-4-                                                                          1-benzyl-9-{2-[4-(hydroxypropyl)-                               (3-hydroxypropyl)-                                                                            1-piperazinyl]ethyl}-1-methyl                                   piperazine                                                      __________________________________________________________________________

                                      TABLE XX                                     __________________________________________________________________________            NO. OF                                                                         EXAMPLE IN                                                                     WHICH STARTING            PRODUCT:                                             MATERIAL IS                                                                               ORGANIC        (PREFIX LISTED BELOW)-1,3,4,9-                EXAMPLE                                                                               PREPARED   HALIDE         TETRAHYDROTHIOPYRANO[3,4-b]INDOLE             __________________________________________________________________________     874    812        (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                         1,1-dimethyl-9-[3-(dimethyl-                                                   amino)propyl]                                 875    812        CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1,1-dimethyl-9-[2-(methylamino)-                                               ethyl]                                        876    812        i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       1,1-dimethyl-9-[2-(isopropyl-                                                  amino)ethyl]                                  877    812        NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                               9-(3-amino-2,2-dimethylethyl)-                                                 1,1-dimethyl                                  878    813        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         9-[2-(dimethylamino)ethyl]-                                                    1-methyl-1-propyl                             879    814        C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         1-ethyl-9-[3-(ethylamino)propyl]                                               1-phenethyl                                   880    815        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-9-[2-(dimethylamino)-                                                 ethyl]-1-methyl                               881    815        CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1-benzyl-1-methyl-9-[2-(methyl-                                                amino)ethyl]                                  882    815        NH.sub.2 (CH.sub.2).sub.3 Cl                                                                  9-(4-aminobutyl)-1-benzyl-1-                                                   methyl                                        883    816        (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2                                               9-[1,2-dimethyl-3-(dimethyl-                                                   amino)propyl]-1,1,3-trimethyl                 884    817        (C.sub.2 H.sub.5 ).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                          Cl             9-[2-(diethylamino)-2-ethyl-                                                   ethyl]-1,3-dipropyl-1-methyl                  885    818        CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                1-cyclopropyl-9-[3-(methyl-                                                    amino)propyl]-1,3,3-trimethyl                 886    819        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-cyclohexyl-3,4-diethyl-9-                                                    [2-(dimethylamino)ethyl]-1-                                                    propyl                                        887    820        (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                                1,4-dimethyl-1,4-dipropyl-9-                                                   [3-(dipropylamino)propyl]                     888    821        (CH.sub.3).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2                                               1-benzyl-9-[2-(dimethylamino)-                                                 2-propylethyl]-1,3,3,4,4-                                                      pentamethyl                                   889    822        (CH.sub.3).sub.2 N[CH(n-C.sub.3 H.sub.7)].sub.3                                CH.sub.2 Cl    1-cyclopropyl-1,5-dimethyl-9-                                                  [4-(dimethylamino)-2,3,4-                                                      tripropylbutyl]                               890    823        (C.sub.2 H.sub.5).sub.2 N(CH.sub.2).sub.2 Cl                                                  1-cyclopentyl-9-[2-(diethyl-                                                   amino)ethyl]-6-ethyl                          891    824        CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                7-methoxy-9-[3-(methylamino)-                                                  propyl]-1,1,3-triethyl                        892    825        n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       8-ethoxy-9-[2-(propylamino)-                                                   ethyl]-1,1,3,3-tetramethyl                    893    826        i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       1,3-diethyl-9-[2-(isopropyl-                                                   amino)ethyl]-6-nitro-1-(3-                                                     phenylpropyl)                                 894    827        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1,1-dimethyl-9-[2-(dimethyl-                                                   amino)ethyl]-8-nitro                          895    828        C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         7-acetoxy-1,4-dimethyl-1-                                                      ethyl-9-[3-(ethylamino)propyl]                896    829        (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-1-cyclopropyl-9-                                                      [2-(dimethylamino)ethyl]-3,3-                                                  dipropyl-6-propionyloxy                       897    830        n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                       5-chloro-1-cyclopropyl-1-methyl-                                               9-[3-(propylamino)propyl                      898    831        1-(3-chloropropyl)-                                                                           1-benzyl-7-chloro-1-cyclohexyl-                                 pyrrolidine    3-methyl-9-[3-(1-pyrrolidinyl)-                                                propyl]                                       899    832        1-(2-chloroethyl)-                                                                            6-bromo-9-(2-piperidinoethyl)-                                  piperidine     1,1,3-triethyl                                900    833        4-(2-chloroethyl)-                                                                            8-bromo-1-methyl-9-(2-morpholino-                               morpholine     ethyl)-1,4,4-tripropyl                        901    834        1-(3-chloropropyl)-                                                                           5-fluoro-1,1,3,3,4,4-hexamethyl-                                piperazine     9-(piperazinopropyl)                          902    835        1-(3-chloroethyl)-                                                                            1-cyclopropyl-7-fluoro-9-                                       4-methylpiperazine                                                                            [2-(4-methyl-1-piperazinyl)-                                                   ethyl]-1-propyl                               903    836        1-(2-chloroethyl)-                                                                            9-{2-[4-(hydroxyethyl)-1-                                       4-(hydroethyl)-                                                                               piperazinyl]ethyl]ethyl-8-iodo-                                 piperazine     1-phenethyl-1,3,4-trimethyl                   904    837        1-(2-chloroethyl)-                                                                            1,1-dimethyl-6-iodo-9-[2-(1-                                    pyrrolidine    pyrrolidinyl)ethyl]                           905    812        1-(3-chloropropyl)-                                                                           1,1-dimethyl-9-(3-piperidino-                                   piperidine     propyl)                                       906    812        4-(4-chlorobutyl)-                                                                            1,1-dimethyl-9-(4-morpholino-                                   morpholine     butyl)                                        907    815        1-(4-chlorobutyl)-                                                                            1-benzyl-1-methyl-9-[4-(4-                                      4-methylpiperazine                                                                            methyl-1-piperazinyl)butyl]                   908    815        1-(2-chloroethyl)-                                                                            1-benzyl-9-{2-[4-(hydroxypropyl)-                               4-(3-hydroxypropyl)-                                                                          1-piperazinyl]ethyl}-1-methyl                                   piperazine                                                   __________________________________________________________________________

EXAMPLE 909 1,1-DIMETHYL-9-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9- TETRAHYDROPYRANO[3,4-b]INDOLE-6-OL [I, R¹ and Y = CH₃, R², R³, R⁴ AND R⁵ = H, R⁶ = OH AND R⁷ = CH₂ CH₂ N(CH₃)₂ ]

5-Benzyloxy-3-tryptophol (II; R², R³, R⁴ and R⁵ = H, R⁶ = 5-benzyloxy and X¹ = OH), m.p. 93° - 95° C., is prepared by lithium aluinum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VIIl R¹ M CH₃), nmr (CDCl₃) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.

The latter compound, 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride (11.5 g., 0.028M) in 600 ml. of absolute ethanol and 600 mg of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere for 22 hr. until no more hydrogen is taken up by the reaction. The catalyst is collected on celite and the filtrate concentrated to afford the corresponding hydrochloric acid addition salt of the title compound, m.p. 225° - 228° C., after recrystallization from ethanol-ether.

The title compound [free base, nmr (CDCl₃) δ1.61 (6H), 2.57 (t, J = 5 cps, 2H), 3.86 (t, J = 5 cps, 2H)] is obtained by decomposing the hydrochloric acid addition salt, for example, by washing a chloroform solution of the salt with 10% sodium hydroxide solution and evaporating the solvent.

By replacing 5-benzyloxy-3-tryptophol with an equivalent amount of 7-benzyloxy-3-tryptophol in the procedure of this example 1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole-8-ol is obtained.

EXAMPLE 910 1-(2-AMINOETHYL)-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X, O and Y = CH₂ NH₂)

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g., 0.817 mole), described in Example 126, is dissolved in dry methylene chloride (400 ml) and freshly prepared triethyloxonium fluoroborate (17.00 g., 0.894 mole) is added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hr.. The methylene chloride solution is washed with cold 75% aqueous potassium carbonate followed by brine and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in ether (150 ml.). The solution is filtered and crystallization proceeds at room temperature to afford ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetimidate, m.p. 139.5° - 141° C.

The latter compound (4.79 g., 0.0176 mole) dissolved in dry THF (100 ml.) is added dropwise to a stirred and ice-cooled suspension of lithium aluminum hydride (1.75 g., 0.046 mole) in THF (50 ml.). The reaction mixture is stirred overnight at room temperature and then dilute sodium hydroxide is added dropwise to decompose excess hydride. The precipitate is collected by filtration and the filtrate is concentrated under reduced pressure thus affording a residue which is extracted with methylene chloride. The organic layers are washed with brine, dried (MgSO₄) and concentration of the solvent and crystallization from ether affords the title compound, m.p. 80° - 84° C., δ_(max) ^(CHCl).sbsp.3 3455, 3280 cm⁻¹, identical with the compound of the same name described in Example 309.

EXAMPLE 911 1-[2-(DIMETHYLAMINO)ETHYL]-9-ETHYL-1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE [I; R¹ = CH₃, R², R³, R⁴, R⁵, AND R⁶ = H, X = S AND Y = CH₂ CH₂ N(CH₃)₂ ]

The compound of formula I in which R⁷ = H and Y = amino(lower)alkyl,1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole (822 mg), described in Example 398, is dissolved in 15 ml of DMF and 15 ml of benzene. To remove all possible traces of water, a portion of this benzene is distilled. After cooling to 0°, 140 mg of sodium hydride (54% suspension in mineral oil) is added, and the mixture stirred for 15 min. Alkylation is accomplished by addition of 350 mg of ethyl bromide and stirring the reaction mixture at 0° for 20 min. The resulting suspension is poured onto cracked ice, extracted with chloroform, the organic layer washed repeatedly with water and evaporated. Chromatography of the residue on silica gel (20 g) using chloroform-methanol (0-10%) affords the title compound, which after crystallization from ether hexane has m.p. 86° - 88° C., δ_(max) ^(CHCl).sbsp.3 2820, 2765, 1600, 1568, 1537 cm⁻¹, nmr (CDCl₃) δ2.20 (s, 6H), 2.30 (m, 4H).

The corresponding hydrochloric acid addition salt of the title compound, 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride, has m.p. 220° - 222° C.

By following the procedure of Example 911 and using an appropriate compound of formula I in which R⁷ is hydrogen and Y is an amino(lower)alkyl, for instance those described in Example 309 to 487, together with the appropriate organic halide, then other compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl are obtained.

For example, the use of the same compound of formula I as described in Example 911 with an equivalent amount of methyl bromide, instead of ethyl bromide, in the procedure of Example 911 gives 1,9-dimethyl-1-[2-(dimethylamino)ethyl]1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, nmr (CDCl₃) δ3.72 (s, 6H), 6.40 (s, 3H), identical to the product of Example 732. The corresponding hydrochloric acid addition salt of this latter compound, 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride has m.p. 244° - 246° C.

Likewise, the use of the same compound of formula I as described in Example 911 with an equivalent amount of propyl bromide, instead of ethyl bromide, gives 1-[2-(dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole. 

We claim:
 1. A process for preparing a compound of formula ##STR93## in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino, 4-(lower)alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X is oxy or thio; and Y is an amino(lower)alkyl of formula Alk-NR⁸ R⁸ in which Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined herein, and R⁸ is hydrogen or lower alkyl and R⁸ is lower alkyl, which comprises:a. reacting in the presence of an inert organic solvent and an acid catalyst selected from the class consisting of p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid and sulfuric acid from 10 minutes to 60 hours at a temperature within the range from 20° C to the boiling point of the reaction mixture substantially equal molar equivalents of a compound of the formula: ##STR94## in which R², R³, R⁴, R⁵ and R⁶ are as defined herein and X¹ is hydroxy or mercapto, with the compound of formula ##STR95## in which R¹ is lower alkyl or lower cycloalkyl and Z is Alk-NR⁸ -COR²¹ in which Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ in which R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined herein, R⁸ is hydrogen or lower alkyl and R²¹ is hydrogen or lower alkyl containing one to five carbon atoms, to provide a tricyclic compound of the formula ##STR96## in which R¹, R², R³, R⁴, R⁵, R⁶, X and Z are as defined herein; b. reducing the tricyclic compound with a suitable complex metal hydride to give the corresponding amine; c. subjecting said amine to N-alkylation with an appropriate organic halide to introduce the R⁷ substituent to give the corresponding compound of the formula ##STR97## in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined herein, Y is Alk NR⁸ CH₂ R²¹ wherein Alk, R⁸ and R²¹ are as defined herein; and, if desired, forming the acid addition salt thereof with a pharmaceutically acceptable acid.
 2. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is ethyl; X is thio; Y is -Alk-NR⁸ -R⁹ wherein Alk is CH₂ CH₂ and R⁸ and R⁹ each is methyl; X¹ is mercapto; and Z is CH₂ CH₂ N(CHO)CH₃.
 3. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is methyl; X is thio; Y is -Alk-NR⁸ R⁹ wherein Alk is CH₂ CH₂ and R⁸ and R⁹ each is methyl; X¹ is mercapto; and Z is CH₂ CH₂ N(CHO)CH₃.
 4. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is methyl; X is oxy; Y is --Alk-NR⁸ R⁹ wherein Alk is CH₂ CH₂ and R⁸ and R⁹ each are methyl; X¹ is hydroxy; and Z is CH₂ CH₂ N(CHO)CH₃.
 5. The process of claim 1 in which R⁷ is lower alkyl.
 6. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is ethyl; X is oxy; Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂, R⁸ is hydrogen and R⁹ is methyl; X¹ is hydroxy; and Z is CH₂ NH(CHO).
 7. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is ethyl; X is thio; Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂, R⁸ is hydrogen, and R⁹ is methyl; X¹ is mercapto; and Z is CH₂ NH(CHO).
 8. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is hydrogen; X is oxy; Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂, R⁸ is hydrogen and R⁹ is methyl; X¹ is hydroxy; and Z is CH₂ NH(CHO).
 9. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is hydrogen; X is thio; Y is --Alk--NR⁸ R⁹ wherein Alk is CH₂, R⁸ is hydrogen and R⁹ is methyl; X¹ is mercapto; and Z is CH₂ NH(CHO).
 10. The process of claim 1 in which R¹ is methyl; R² to R⁶ inclusive are hydrogen; R⁷ is hydrogen; X is oxy; Y is --AlkNR⁸ R⁹ in which Alk is CH₂ CH₂, R⁸ is hydrogen and R⁹ is methyl; X¹ is hydroxy; and Z is CH₂ CH₂ NH(CHO). 